1. Introduction
The quintessential example of bone loss is osteoporosis, affecting 12.6% of US adults over 50 years old, with a higher prevalence among women at 19.6% [ 1 ]. While the cause of osteoporosis varies with its pathophysiological etiologies, primary osteoporosis is associated with enhanced bone resorption secondary to postmenopausal estrogen deficiency, leading to fragile bones [ 2 ]. Indeed, a 2019 US prospective cohort study by Ensrud et al. demonstrated that women older than 80 years diagnosed with osteoporosis had a 5-year hip fracture probability threefold higher than their non-osteoporotic counterparts [ 3 ]. Osteoporosis presents a significant burden to patients, their families, and health systems globally. Fragility hip fractures are associated with $10,075 worth of in-hospital costs, totaling $43,669 at 12 months [ 4 ]; furthermore, all-cause mortality of hip fractures is around 22% at 1 year [ 5 ]. Besides antiresorptive, pharmacological treatment, the American Academy of Orthopaedic Surgeons recommends that surgical intervention be taken as soon as medically feasible for patients who sustain hip fragility fractures [ 6 ]. Convalescence is further complicated by a risk of prosthetic joint loosening, with about 10% requiring re-operation within 15 years. Half of these revisions will take place secondary to periprosthetic osteolysis, causing aseptic loosening [ 7 , 8 ]. Beyond the hip, a 2019 meta-analysis of the global burden of bone fractures found there were 178 million new fractures with a 65.3% increase in years lived with disease since 1990 [ 9 ]. Elucidating the cellular mechanisms of bone homeostasis can lead to improved healthcare outcomes for patients with metabolic bone disease, fractures, and those undergoing orthopedic intervention involving implants.
A number of other pathologies, including rheumatoid arthritis (RA) and periodontitis, are also characterized by bone loss. During RA, pro-inflammatory cytokines such as TNF-α, IL-1β, and RANKL, produced by activated T-cells and synovial fibroblasts, directly stimulate bone resorption [ 10 ]. This is exacerbated by auto-antibodies found in RA [ 11 ], leading to focal bone erosions and periarticular osteopenia. Inflammatory factors of RA also impair bone repair, furthering net bone losses [ 11 ]. This all contributes heavily to the long-term sequelae of RA, including progressive joint destruction, deformities, and increased risk of fragility fractures, causing physical disability and significant decreases in quality of life [ 12 ]. RA is also a well-established risk factor for osteoporosis, tying it to all of the burdens listed above. A similar mechanism is seen in periodontal disease, except in this case, bacterial dysbiosis increases pro-inflammatory cytokine levels and bone resorption by triggering the host immune response [ 13 ]. In contrast to RA, bone loss during periodontal disease tends to be more local, characterized by alveolar bone loss which leads to edentulism [ 13 ].
Bone remodeling is facilitated through a continuous cycle of resorption and formation, which becomes unbalanced within disease contexts. This highly coordinated cycle relies on the balance between multiple cellular participants within the bone remodeling unit including: osteoclasts, osteoblasts and osteocytes ( Figure 1 ) [ 14 ]. Osteoclasts are multinucleated cells derived from osteoclast progenitors of the monocyte/macrophage lineage. Osteoclasts function to resorb and degrade bone at sites of damage during bone remodeling [ 15 ]. These monocyte/macrophage cells fuse together in response to cytokine and receptor stimuli to form multinucleated osteoclasts [ 16 , 17 ]. CSF1-CSF1R, IL-34-CSF1R, and RANK-RANKL cytokine-receptor bindings provide signals for proliferation of precursors and stimulate the differentiation and resorptive functions. These cytokines also aid the survivability and maintenance of pre-osteoclasts and mature osteoclasts [ 18 ]. Osteoblasts are involved in various processes including the production of bone matrix proteins, mineralization of bone, and the expression of osteoclastogenic factors [ 19 ]. A subset of osteoblasts will undergo further differentiation and become bone-encased osteocytes [ 20 ].
There are five key phases involved during the bone remodeling process; these include (1) activation, (2) resorption, (3) reversal, (4) formation, and (5) termination. During activation, either mechanical strain or hormone signaling initiate bone remodeling [ 14 ]. When mechanical strain is put on the bone, osteocytes are responsible for sensing changes and using various dendritic processes to signal other cells to initiate bone remodeling [ 21 ]. Resorption ensues after activation and is accomplished by mature osteoclasts that developed from the precursors recruited during activation [ 21 ]. Following resorption, the reversal phase couples bone resorption to formation through the creation of an osteogenic environment at remodeling sites. The reversal phase begins when osteogenic signals are released from osteoclasts. These signals reach nearby cells, including bone marrow and bone surface cells. These bone lining cells on quiescent bone surfaces retract in order to allow the osteoclasts to have access to the bone matrix. Other cells termed reversal cells cover around 80% of the eroded surface [ 22 ]. There is a lack of knowledge about how the cells included in the reversal phase operate and the origins of osteoprogenitors [ 22 ]. This is a critical area of research, as development of biomaterials supporting bone formation could be greatly improved. The reversal phase is followed by formation, the longest phase of bone remodeling, which begins with the migration of osteoblasts to the resorption lacunae, stimulated by Wnt signaling [ 14 ]. Then, osteoblasts mediate osteogenesis. Following mineralization, osteoblast cells undergo apoptosis or change their function by becoming osteocytes embedded in the bone or lining cells that lay flat in quiescence. This marks termination, the last stage of bone remodeling [ 21 ].
In addition to hematopoietic progenitors, osteoclasts that facilitate bone resorption can be derived from other sources of progenitors. This includes embryonic erythromyeloid progenitors (EMPs) and potentially other non-canonical osteoclast progenitors such as osteomorphs and osteomacs. Osteomorphs are a newly discovered osteoclast lineage cell type in mice, which have a significant role in bone resorption. A study by McDonald et al. demonstrated that multinucleated osteoclasts could undergo fission to form smaller, motile daughter cells, termed osteomorphs [ 23 ]. Osteomorphs can circulate in blood and can also re-fuse to form osteoclasts, an alternate fate to apoptosis. In contrast, osteomacs are a subset of bone-resident macrophages that have been discovered as an important regulator of bone remodeling along with osteoblasts, osteoclasts, and osteocytes. Osteomacs constitute one-sixth of all bone marrow cells forming canopy-like structures within bone remodeling sites in the calvarium to support osteoblast survival, differentiation, and mineralization [ 24 ]. Studies suggest that they may influence osteoblast-driven mineralization and, under pathological conditions, act as a precursor for multinucleated giant cells [ 25 , 26 , 27 ]. This highlights the plasticity and the potential role of osteomacs in coupling osteoblast and osteoclast activity.
Traditionally, osteoclasts were thought to arise solely from hematopoietic stem cell-derived progenitors, but our understanding of the different developmental sources and their respective role in normal physiology, site-specific remodeling, and pathology is evolving. Because there are potentially unique osteoclast progenitors that orchestrate bone resorption/remodeling under different contexts, identifying and characterizing these cells is key to providing tailored therapies.
2. Sources of Osteoclast Progenitors
A growing body of research supports that there are multiple sources of osteoclast progenitors and that these pools vary across the lifespan and during different disease states (see Figure 2 for an overview). These osteoclast progenitors include EMPs and hematopoietic stem cell (HSC)-derived precursors. Osteoclast progenitors can arise from bone marrow-resident cells, mobilized splenic cells, as well as circulating peripheral blood monocytes. There is also budding evidence to support so-called non-canonical osteoclast progenitors, including osteomorphs and osteomacs.
2.1. Developmental Origins of Osteoclast Progenitors
Hematopoietic stem cells give rise to osteoclast progenitor cells. Bone marrow transplantation studies that demonstrate functional recovery of osteopetrosis in humans support the HSC origins of osteoclast progenitors [ 28 , 29 , 30 ]. Further studies in mice confirmed that osteoclast progenitors derived from HSCs originate from the bone marrow and spleen [ 31 , 32 , 33 ].
More recent evidence demonstrates that osteoclast progenitors also derive from erythromyeloid progenitors. Osteoclasts derived from embryonic EMPs seed neonatal bone, enabling marrow cavity formation and colonization of the bone marrow by hematopoietic stem cells and definitive hematopoiesis [ 34 , 35 , 36 , 37 , 38 ]. Lineage tracing studies in mice suggest that both early EMPs arising from the yolk-sac and late EMPs derived from the fetal liver serve as osteoclast progenitors (5). These EMP-derived progenitors give rise to osteoclast populations that persist into postnatal life and participate in both physiological remodeling and bone repair after injury [ 34 , 39 ]. EMP differentiation is independent of postnatal HSCs, but evidence suggests that EMP-derived osteoclasts may fuse with HSC-derived progenitors postnatally [ 34 ]. While there is much evidence to suggest that EMPs contribute to osteoclasts in pre-clinical models, existence of EMPs of embryonic origin in humans and their ability to form osteoclasts during embryonic development is unknown. In other organ systems, induction of embryonic phenotypes can rejuvenate tissue [ 40 , 41 , 42 ]. It is therefore tempting to speculate that induction or delivery of EMPs could attenuate pathological bone loss by rejuvenating bone-resorbing osteoclasts.
2.2. Bone Marrow-Resident OCPs
Bone marrow-resident cells constitute the dominant source of osteoclast progenitors under homeostatic conditions. These populations often support macrophage and dendritic cell differentiation as well [ 43 ]. Early fractionation studies in mice suggested the existence of multiple osteoclast precursor populations within the bone marrow [ 44 , 45 , 46 , 47 ], but this work did not identify direct progenitors or rule out macrophage differentiation. Other studies demonstrate that bone marrow-resident subsets define the predominant source of osteoclasts for steady-state remodeling, forming functional multinucleated osteoclasts dependent on mesenchymal stem cell interactions using murine models [ 39 , 48 ]. These marrow-derived cells reside within specialized stromal niches and are regulated by local mesenchymal stem cells (MSCs) and signaling molecules such as RANKL and CSF1, with Adipoq + cells within the bone marrow potentially serving as the predominant source of CSF1 and RANKL [ 49 , 50 , 51 , 52 ]. Although most of these studies were performed in mice, they clearly document that bone marrow-resident progenitors contribute to osteoclastogenesis.
2.3. OCPs Within the Circulation
Under pathological conditions, such as inflammatory arthritis, bone metastasis, or advanced age, circulating peripheral blood monocytes are increasingly recognized as key contributors to dysregulated osteoclast activity. These cells, including CD14 + and CCR2 high subsets, are recruited to inflammatory bone environments via chemokine-mediated mechanisms, notably the CCL2/CCR2 axis [ 53 , 54 , 55 , 56 ]. Experimental blockade of this signaling axis reduces pathological osteoclastogenesis and bone resorption in mouse models of arthritis [ 53 ]. Further evidence from both human and murine systems confirms that peripheral blood-derived precursors can differentiate into functional osteoclasts in the absence of stromal support, highlighting their autonomously osteoclastogenic potential in inflammation. In addition to peripheral blood monocytes, myeloid-derived suppressor cells (MDSCs) can also function as a source of osteoclast progenitors in the context of cancer-induced osteolysis [ 57 ]. Intravital imaging studies likewise demonstrate that osteoclast precursors traffic through the bone vasculature, suggesting that cells from the circulation can participate in bone remodeling [ 58 ].
Circulating osteoclast progenitors can also originate from mobilized splenic cells. In vitro studies demonstrate that cells isolated from the spleen can support osteoclastogenesis [ 59 , 60 ]. Moreover, osteopetrotic mice lacking bone marrow-resident OCPs acquire osteoclasts with age in an IL-34-dependent mechanism, which was abrogated via splenectomy [ 61 ]. Using photoconversion-based cell tracking, marked cells were shown to traffic from the spleen to form labeled osteoclasts lining long bone surfaces [ 62 ]. Lineage tracing studies likewise demonstrate that the spleen is a source of osteoclast progenitors [ 36 ]. Combined, these studies demonstrate that peripheral osteoclast progenitors arise both from bone marrow-dependent sources as well as cells mobilized from the spleen.
2.4. Non-Canonical Osteoclast Progenitors
Two putative sources of OCPs include osteomorphs and osteomacs. Both osteomorphs and osteomacs have been experimentally characterized as non-canonical osteoclast progenitor populations that influence bone remodeling. In vitro evidence suggested that osteoclasts not only form via fusion, but can undergo fission [ 63 ]. This process can be induced by the soluble RANKL decoy receptor, Osteoprotegerin (OPG, TNFRSF11B, TR1, OCIF, PDB5) [ 23 ]. Studies utilizing in vivo fate-mapping and photoconversion labeling demonstrated that multinucleated osteoclasts undergo fission in vivo leading to osteomorph formation [ 23 ]. These cells rapidly re-fuse to restore bone resorption in response to RANKL [ 23 ]. Moreover, the osteomorph pool size quantitatively dictated the timing and magnitude of resorption “rebound” after anti-RANKL therapy withdrawal, establishing a direct functional link to bone remodeling outcomes. In contrast, the direct effect of osteomorphs on bone formation (osteoblast activity/mineralization) remains unexplored. Although the existence of osteomorphs may explain rapid bone loss associated with discontinuation of anti-RANKL therapy [ 23 ], evidence supporting osteomorphs within humans is also lacking.
Osteomacs are bone marrow-resident macrophages that support bone formation. A few key studies support that osteomacs display context-dependent plasticity to support osteoclastogenesis and promote coupling between resorption and formation [ 64 , 65 , 66 ]; however, this is under strong RANKL/M-CSF concentrations. Post-menopausal bone loss (i.e., ovariectomy models) shows increased osteomac numbers tightly associated with areas of heightened bone resorption and decreased formation [ 67 ], but direct osteomac-to-osteoclast differentiation remains limited to inference or rare events. Clear in vivo fate-mapping of osteomac-to-osteoclast conversion is needed to provide definitive evidence that osteomacs serve as non-canonical osteoclast progenitor pools. In contrast, in vivo evidence in mice and humans suggests that the major role of osteomacs is to support coupling rather than bulk replenishment of differentiating osteoclasts [ 24 , 66 , 68 ].
Collectively, these studies converge on a model in which distinct osteoclast progenitor sources are differentially engaged depending on developmental timing and disease context, each regulated by unique molecular and environmental cues. Emerging work suggests that embryonic progenitors possess persistent functional roles into adulthood [ 36 ] while circulating monocytes become dominant under inflammatory states [ 53 ], and that bone marrow-resident progenitors maintain bone turnover under baseline conditions [ 39 , 45 , 48 ]. However, direct comparative analyses of molecular profiles and functional outcomes across all three progenitor populations remain limited, particularly under pathological conditions. Continued investigation is needed to elucidate the regulatory mechanisms that specify osteoclast differentiation from these distinct progenitor compartments.
3. Defining Surface Markers of Osteoclast Progenitors
Osteoclast progenitors are cells that directly fuse to form multinucleated, bone resorbing cells. Osteoclast progenitor cells must respond to RANKL and M-CSF, but unfortunately the receptors for these cytokines, RANK and CD115 (Csf1r, c-fms), are expressed by other types of bone marrow resident cells as well as cells within the periphery. CD115 is broadly expressed by cells within the myeloid lineage, including osteoclasts, dendritic cells, as well as monocytes and macrophages, including tissue-resident cells as well as those within the circulation. RANK is mainly expressed by osteoclast precursors, mature osteoclasts, and immune cells such as DCs, macrophages, T cells, and microglia [ 69 ]. Expression is also detected in some epithelial cells in the small intestine [ 70 ], mammary glands [ 71 ], and some cancer cell types [ 72 ]. As such, additional surface markers are needed to define osteoclast progenitors. While many groups have identified osteoclast progenitors surface markers, a definitive characterization is still lacking. This may be because these cells are highly plastic and/or that multiple osteoclast precursors are present within different physiological and disease contexts. Below we discuss how several surface markers ( Figure 3 ) have been used alone or in conjunction with others to isolate cells with osteoclastogenic potential from different anatomical sites and/or disease states.
CD11B/ITGAM (CDR3A, MO1A, MAC-1, MAC1A, SELB6) encodes the integrin alpha protein expressed by immune cells, including myeloid and lymphoid cells, as well and microglia within the brain and endothelial cells. ITGAM helps to facilitate leukocyte migration and infiltration. Because of its expression by monocyte/macrophage cells, CD11B was used early as a surface marker to enrich osteoclast progenitor populations. Both CD11B + and CD11B −/low populations, in combination with other surface markers, can be used to isolate bone marrow-resident and/or circulating osteoclastogenic cells from mice [ 45 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. CD11B + peripheral cells were mostly identified in studies concerned with inflammatory bone loss, including TNF-α-driven bone loss or within models of experimentally induced rheumatoid arthritis [ 74 , 76 , 78 , 79 ]. In contrast, CD11B −/low bone marrow osteoclast progenitor cells were identified in homeostatic conditions. Most human studies use human blood to identify osteoclast progenitors and are most frequently found in the CD11B + CD14 + monocyte pool in adults [ 78 , 80 ]. In addition, studies using human cells of embryonic origin have identified CD11B as a marker for osteoclastogenic progenitors [ 43 , 47 ]. Overall, CD11B can be used in combination with additional markers (e.g., c-kit, CD115, Ly6c, lineage exclusion) to isolate osteoclast progenitors, but positive expression seems to delineate between OCPs involved in pathological versus physiological bone remodeling, respectively.
CSF1R (Fms, c-fms, Fim2, Csfmr, Cd115, M-CSFR) is the receptor for CSF1/M-CSF and IL-34 and is expressed by monocyte/macrophage cells with osteoclastogenic potential. CSF1R mediates the activation of multiple downstream kinases, including MEK/ERK, PI3K/Akt, JAK/STAT, and PLC. CD115-based positive selection identifies osteoclast progenitors in mice that form TRAP-positive multinucleated osteoclasts in vitro [ 81 , 82 , 83 , 84 ]; however, CD115 marks multiple hematopoietic lineage cells. Given this, most studies utilize CD155 positive selection in conjunction with additional surface markers to enrich osteoclast progenitors.
CD45R (B220, Cd45, L-CA, Ly-5, Lyt-4, Ptprc, T200) is broadly expressed by hematopoietic cells, but may be a defining surface marker to isolate the osteoclast progenitor pool. CD45 is a phosphatase that regulates activation of Src kinases. Early studies suggested that CD45R marked bone marrow-resident cells that formed osteoclasts in vitro in response to CSF1 and RANKL [ 73 ]. Moreover, the authors demonstrated that CD45R + bone marrow-resident cells, but not CD45R − cells, expanded following ovariectomy [ 73 ]. In contrast, later studies by this group demonstrated that highly purified CD45R + cells did not support osteoclastogenesis [ 45 ]. Instead, CD115 + CD117 + (Csf1r + C-kit + ) bone marrow resident cells were identified, but the authors noted that CD117 was downregulated during osteoclast differentiation, indicating that these cells may not be direct osteoclast progenitors [ 45 ]. Further experiments demonstrated that FACS-sorted CD11B −/low CD45R − CD3 − CD115 high Cd117 + murine bone marrow cells contained the highest osteoclastogenic potential. This was corroborated by a study demonstrating that murine bone marrow CD45 − CD3 − CD11B −/low Ly6c high cells demonstrated high osteoclastogenic potential that was exacerbated when cells were derived from animals with experimentally induced rheumatoid arthritis [ 74 ].
Other surface markers have likewise been used to isolate purified osteoclast progenitors. Peripheral monocytes are characterized by high surface expression of CD14 in the periphery in humans, with Ly6C serving as the mouse equivalent. As such, CD14 also marks peripheral osteoclast progenitors. Multiple rigorous studies in mice utilize c-Kit (CD117) in combination with other surface markers as a prospective positive selection strategy to isolate osteoclast progenitor populations from bone marrow and peripheral sources in mice and humans [ 47 , 85 , 86 , 87 ]. The chemokine receptor CX3CR1 is also a marker of osteoclast progenitors. Evidence using lineage tracing models demonstrates that CX3CR1 marks a pool of osteoclast progenitors in mice [ 37 , 39 ]. Although CX3CR1 marks osteoclast progenitors, several studies also demonstrate that these cells have multilineage potential and can generate macrophage and dendritic cell lineages in addition to osteoclasts.
Given that the evidence for both bone marrow-resident and circulating osteoclast progenitors in different developmental and disease-specific settings, surface markers used for the isolation of these cells may be context dependent. Although direct evidence is lacking, isolation of Lin − Ly6g − CD11B −/low Ly6c int/+ CD115 + c-Kit + F4/80 low cells from whole bone marrow may reflect the resident osteoclast progenitors derived from murine sources. CD45 −/low CD115 + myeloid cells with co-expression of Ly6C high or CCR2 high , from blood likewise show robust CSF1/RANKL-dependent osteoclastogenesis, but further addition of Cx3cr1 may help to refine selection of osteoclast progenitors from peripheral blood.
4. OCP Changes During Disease, Injury, and Age-Associated Bone Loss
4.1. Changes to Osteoclast Progenitors with Advanced Age
Osteoclast progenitors both increase in number and have higher intrinsic osteoclastogenic potential with advanced age [ 88 , 89 , 90 , 91 ]. In a study using CD14 + cells isolated from the peripheral blood of women aged 49–66, age and menopausal status was shown to be positively associated with increased bone resorption in vitro [ 92 ]. Moreover, an epigenetic analysis of peripheral CD14 + cells suggested that increasing years post-menopause resulted in diminished DNA methylation of gene promoters of DC-STAMP and CTSK, genes associated with osteoclastogenesis and resorption, respectively [ 92 ]. In addition, circulating OCPs were found to have greater osteoclastogenic potential than other myeloid cells and that the frequency and activity of osteoclast progenitors negatively correlates with bone mass in post-menopausal women [ 93 , 94 ]. Moreover, estrogen suppresses the number of circulating OCPs in post-menopausal women [ 95 ].
Many studies demonstrate that the number of osteoclast progenitors increases with advanced age, both in pre-clinical models as well as in humans, along with age-related bone loss. With age, the composition of bone marrow shifts to diminished proportions of adaptive immune cells, increased adiposity, and enhanced myelopoiesis [ 88 , 89 ]. The expansion of myeloid cells with age includes myeloid-derived suppressor cells (MDSCs) that can serve as osteoclast progenitors [ 96 , 97 ]. Further analyses demonstrated that MDSCs were expanded within peripheral tissues, but not within the bone marrow, of aged mice [ 98 ]. In contrast, other studies demonstrate increased numbers of monocyte/macrophage cells within the bone marrow of aged mice [ 99 ]. This suggests that both bone marrow-resident and peripheral osteoclast progenitors expand with advanced age.
Other studies suggest that the mesenchymal compartment of the bone marrow supports myeloid skewing [ 100 ]. For instance, clearing of p16-expressing senescent osteoclast progenitors did not influence bone mass in a pre-clinical model, suggesting that other cell types, most notably osteocytes, may be responsible for age-related declines within the skeleton [ 90 ]. Changes in skeletal stem cells with advanced age were likewise shown to support an inflammatory microenvironment within the bone marrow that led to myeloid skewing and reduced bone regeneration [ 101 ]. Overall, studies support that osteoclast progenitor number and osteoclastogenic potential increase with age, but the underlying causes for this are still under study.
4.2. Osteoclast Progenitors Participating in Bone Healing Following Injury
Proper bone healing following injury requires the actions of osteoclasts. During endochondral fracture healing, osteoclasts aid in bone healing as part of the early and late phases [ 102 , 103 ]. This is likewise true of intramembranous bone healing of cortical defects [ 68 ], but clearance of osteoclasts via OPG treatment did not limit cortical bone defect healing; however, this conclusion was based on histological assessment alone at a single time point (e.g., 9 days post defect generation). Laser ablation studies likewise show that osteoblast injury precipitates an inflammatory response leading to the recruitment of immune cells and the formation of cathepsin K + cells in zebrafish, with anti-inflammatory treatment limiting osteoblast recovery following injury [ 104 ].
There are several origins of osteoclasts that participate during bone healing. Parabiosis studies coupled with flow cytometry analyses in mice support that circulating Cx3cr1 + osteoclast progenitors participate in endochondral fracture healing [ 39 ]. In a separate study, parabiosis experiments coupled with single cell sequencing analyses also demonstrated that Cx3cr1 marks a population of erythromyeloid progenitors within the spleen that can be mobilized to participate in bone healing following injury [ 36 ]. Studies from a fracture healing model using medaka suggested that two populations of osteoclasts participate in early and late phases of bone healing, with the presence of a sealing or clear zone defining osteoclasts within the late phase of healing [ 103 ]. This observation suggests heterogeneity during the bone healing process and the potential for more than one progenitor source during different phases of healing [ 103 ].
Osteoclast progenitors participate in bone healing not only through the formation of bone-resorbing osteoclasts, but may also promote osteogenesis required for ossification following injury. In a study focusing on TRAP + lineage cells, osteoclast progenitor cells were suggested to promote neovascularization and bone formation via PDGF-BB in a pre-clinical model of osteoporosis [ 105 ]; however, the exact cell type mediating this effect is unclear. Other studies identified periosteal osteoclast precursors promoting fracture healing through PDGF-BB in a cathepsin K-independent manner [ 106 ].
Osteoclasts not only participate during bone healing, but may also be needed for limb regeneration as well as integration of dental and orthopedic implants. Studies using a model of natural limb regeneration in axolotl demonstrate that osteoclasts prime the skeleton for successful regeneration and blocking their function limits limb regeneration [ 107 ]. Pre-clinical evidence also supports that integration of dental and orthopedic implants likewise requires the action of osteoclasts to aid in the resorption of necrotic bone, initiate bone formation at the implant interface, as well as during the late phases of implant integration [ 108 , 109 , 110 , 111 , 112 , 113 ]. Conversely, osteoclasts also contribute to implant loosening associated with debris wear particle production [ 114 , 115 ]. The developmental origins and sources of osteoclast progenitors mediating these processes are areas for further research.
4.3. Osteoclast Progenitors in Rheumatoid Arthritis
Whereas adult osteoclasts are predominantly HSC-derived and sourced from bone-marrow–resident progenitors during homeostasis, rheumatoid arthritis recruits osteoclast progenitors from additional sources resulting in the destruction of subchondral bone. This includes HSC-derived cells from the periarticular bone marrow, circulation, and spleen [ 53 , 74 , 77 , 116 , 117 , 118 ]. Expansion of osteoclast progenitors defined by surface marker expression of CD11B −/low CD117 + CD115 + or high levels of CCR2 within the periarticular bone marrow space contributes to bone erosion associated with RA [ 53 , 77 , 119 ]. Studies using human peripheral blood also demonstrate that circulating osteoclast progenitors defined by CD11B/CD14 also expand with RA [ 120 ]. This is further corroborated by studies in mice demonstrating that peripheral and splenic OCPs expand in models of RA and that adoptive transfer of OPCs derived from the spleen hone to RA sites through a CCL2/CCR2-dependent mechanism [ 53 ]. Moreover, high levels of circulating TNF-α lead to expansion of circulating osteoclast progenitors [ 121 ], which may serve as a source of RANKL-independent osteoclastogenesis via a TGF-β-dependent mechanism [ 122 ]. In addition to bone marrow-resident and circulating OCPs, macrophages within synovium may also serve as a source of osteoclast progenitors. These arthritis-associated osteoclastogenic macrophages (AtoMs) are present within the inflamed synovium and intravital imaging in mice demonstrates their differentiation in situ to TRAP + cells [ 116 , 117 , 118 ]. Despite these advances in our understanding of osteoclast progenitors that contribute to bone erosion in the setting of rheumatoid arthritis, studies largely lack definitive lineage tracing to quantify contributions of specific progenitors. Likewise, human tissue-level in vivo evidence of specific OCP subsets forming erosive osteoclasts remains limited.
4.4. Osteoclast Progenitors in Periodontitis
Increased osteoclast activity contributes to bone loss associated with periodontal disease. There are no definitive studies that demonstrate the developmental origins that contribute to osteoclast progenitors in the context of periodontal disease. In contrast, CD11B + c-Fms + Ly6C high cells within the bone marrow, spleen, and peripheral expansion in response to chronic Porphyromonas gingivalis exposure implicate cells of hematopoietic origin [ 75 , 123 ]. Moreover, increased levels of CCl2 within the gingival crevicular fluid are associated with periodontitis, suggesting recruitment of osteoclast progenitors from the periphery [ 124 ]. Numerous studies also demonstrate that peripheral blood monocytes from periodontitis patients have enhanced osteoclastogenic capacity [ 125 , 126 , 127 , 128 , 129 ]. We discuss below how immune priming can enhance bone resorption in case of chronic periodontitis.
4.5. Impacts of Trained Immunity on Osteoclast Progenitors
Bone loss associated with chronic inflammatory diseases, such as periodontitis and arthritis, is driven in part by dysregulated osteoclastogenesis initiated in the innate immune compartment. A growing body of evidence implicates trained immunity—a memory-like state of the innate immune system induced by microbial components such as lipopolysaccharide (LPS), β-glucan, and live or inactivated pathogens—in the functional reprogramming of osteoclast progenitors (OCPs). This reprogramming includes persistent alterations in surface marker expression, metabolic activity, epigenetic profile, and bone-resorptive potential.
Studies using pre-clinical models have elucidated critical aspects of this relationship. Repeated or chronic exposure to the periodontal pathogen Porphyromonas gingivalis has been shown to expand a CD11B + c-Fms + Ly6C high population with enhanced osteoclastogenic activity within bone marrow, spleen, and blood [ 123 ]. These inflammatory OCPs also exhibit altered transcriptional profiles related to differentiation, inflammation, and apoptosis [ 75 , 76 ]. Similarly, in arthritis models, disease-associated expansion of CCR2 high OCPs was observed, with transcriptomic profiling revealing osteoclast-priming signatures enriched in pathways such as chemokine and NOD-like receptor signaling [ 53 ]. Studies in the context of collagen-induced arthritis further revealed enhanced migratory capacity and osteoclastogenic potential of CD11B + CD115 + and CD11B low CD115 + subsets under inflammatory conditions, with significant changes in chemokine receptor expression [ 77 ].
At the mechanistic level, trained immunity has been causally linked to histone modifications (e.g., H3K4me3, H3K27ac) and metabolic shifts, such as increased glycolysis and TCA cycle flux, among myeloid progenitors exposed to β-glucan or Bacille Calmette–Guérin (BCG) [ 78 , 79 ]. These alterations confer long-lasting amplification of inflammatory outputs and cellular responsiveness. In vitro systems modeling trained macrophage-mediated osteoclastogenesis confirm that immune memory alters cytokine production (e.g., TNF-α, IL-6) and influences osteoclast differentiation in co-cultures [ 80 , 130 ]. Key signaling pathways included TNF-α/S100A8/A9, MyD88/NF-κB, and mTOR, all amplifying responses to RANKL and inflammatory cues [ 130 , 131 ]. Longitudinal in vivo analysis also suggests β-glucan priming of monocytes can extend functional changes for weeks, partially through survival enhancement and transcriptional reprogramming [ 132 ].
Taken together, these studies converge on the concept that trained immunity, as induced by microbial or inflammatory stimuli, permanently reshapes the osteoclast precursor landscape through both phenotypic transformation and molecular remodeling. Chronic inflammation reinforces osteoclastogenic potential at the progenitor level, providing a mechanistic link between innate immune memory and sustained bone loss in inflammatory diseases. Despite these advancements, further research is needed to establish the temporal persistence of trained immunity and the cumulative effects during aging or recurrent inflammation.
4.6. Osteoclast Progenitors in Osteoarthritis (OA)
Subchondral bone remodels in a time-dependent fashion during osteoarthritis disease progression. This includes diminished subchondral bone mass early during OA as well as enhanced or sclerotic bone late during joint degeneration [ 133 ]. Roles for bone resorption in OA progression are supported by studies demonstrating that anti-resorptive agents have effects on OA progression [ 134 ]. Current evidence suggests that osteoclast progenitors may contribute to OA progression by disrupting the osteochondral junction [ 135 , 136 , 137 , 138 ]. Human evidence supports that vascular channels traverse into cartilage in OA specimens [ 136 ]. Further studies in mice document that increased osteoclast progenitor-produced PDGF-BB drives type H vessel growth into the osteochondral junction [ 135 , 137 , 138 ]. To date, there is no definitive evidence that defines the developmental or anatomical origins of osteoclast progenitors that facilitate altered subchondral bone remodeling associated with OA. Recruitment routes of osteoclast progenitors to subchondral bone remodeling sites is likewise still under investigation. These are all areas for future research that would greatly enhance our understanding of OA pathogenesis.
5. Conclusions
In this narrative review, we provided an overview of the developmental sources, defining surface markers, and changes to osteoclast progenitors that occur in various conditions. While we aim to be comprehensive, our review of the field has several limitations. We acknowledge that various cancer cell types, including lung, breast and prostate cancer, frequently metastasize to bone and promote osteolysis. Other cancer types, including oral squamous cell carcinoma, osteosarcoma and multiple myeloma, are also characterized by altered bone remodeling. Offering a comprehensive review of how osteoclast progenitors change in each of these specific cancers is beyond the scope of this review. Our narrative review is also a biased summary of the field and is not comprehensive of all literature within the field that would be achieved by performing systemic review on a narrower research topic. Our understanding of osteoclast progenitors is limited due to a lack of unique markers, heterogeneity, limited numbers in vivo, and difficulty in studying these cells within their native niche(s). Combined approaches utilizing single cell sequencing, single cell epigenetics, and spatial transcriptomics could help to address these restrictions.
While we have made large advances in our understanding and treatment of conditions characterized by changes in the bone remodeling process, understanding how different osteoclast progenitors contribute to normal and pathological bone loss is still a key area for future research. Defining specific OCP surface markers that are associated with different disease contexts and conditions will allow us to understand how OCPs differ as compared to those involved in physiological bone remodeling. This could further aid the characterization of OCP types and development of tailored therapeutics.
Acknowledgments
Biorender software was used to generate figure images. During the preparation of this manuscript/study, the authors used undermind.ai for the purposes of collecting references documenting findings within the text. The authors have reviewed and edited the output and take full responsibility for the content of this publication.
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Author Contributions
Conceptualization, M.J.S. and E.W.B.; methodology, M.J.S., G.K., I.Y.K., E.K.V., E.C., J.C.M., E.P., A.B., K.C.V., S.M., J.K. and E.W.B.; writing—original draft preparation, M.J.S., G.K., I.Y.K., E.K.V., E.C., J.C.M., E.P., A.B., K.C.V., S.M., J.K. and E.W.B.; writing—review and editing, M.J.S., G.K., I.Y.K., E.K.V., E.C., J.C.M., E.P., A.B., K.C.V., S.M., J.K. and E.W.B. All authors have read and agreed to the published version of the manuscript.
Data Availability Statement
No new data were created or analyzed in this study. Data sharing is not applicable to this article.
Conflicts of Interest
The authors declare no conflicts of interest.
References
1. Sarafrazi N. Wambogo E.A. Shepherd J.A. Osteoporosis or Low Bone Mass in Older Adults: United States, 2017–2018 NCHS Data Brief 2021 1 8 34029181
2. Ji M.X. Yu Q. Primary osteoporosis in postmenopausal women Chronic Dis. Transl. Med. 2015 1 9 13 10.1016/j.cdtm.2015.02.006 29062981 PMC5643776
3. Ensrud K.E. Kats A.M. Boyd C.M. Diem S.J. Schousboe J.T. Taylor B.C. Bauer D.C. Stone K.L. Langsetmo L. Study of Osteoporotic Fractures Research G. Association of Disease Definition, Comorbidity Burden, and Prognosis With Hip Fracture Probability Among Late-Life Women JAMA Intern. Med. 2019 179 1095 1103 10.1001/jamainternmed.2019.0682 31206140 PMC6580441
4. Williamson S. Landeiro F. McConnell T. Fulford-Smith L. Javaid M.K. Judge A. Leal J. Costs of fragility hip fractures globally: A systematic review and meta-regression analysis Osteoporos. Int. 2017 28 2791 2800 10.1007/s00198-017-4153-6 28748387
5. Sing C.W. Lin T.C. Bartholomew S. Bell J.S. Bennett C. Beyene K. Bosco-Levy P. Bradbury B.D. Chan A.H.Y. Chandran M. Global Epidemiology of Hip Fractures: Secular Trends in Incidence Rate, Post-Fracture Treatment, and All-Cause Mortality J. Bone Miner. Res. 2023 38 1064 1075 10.1002/jbmr.4821 37118993
6. O’Connor M.I. Switzer J.A. AAOS Clinical Practice Guideline Summary: Management of Hip Fractures in Older Adults J. Am. Acad. Orthop. Surg. 2022 30 e1291 e1296 10.5435/JAAOS-D-22-00125 36200817
7. Goodman S.B. Gallo J. Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment J. Clin. Med. 2019 8 2091 10.3390/jcm8122091 31805704 PMC6947309
8. Hodges N.A. Sussman E.M. Stegemann J.P. Aseptic and septic prosthetic joint loosening: Impact of biomaterial wear on immune cell function, inflammation, and infection Biomaterials 2021 278 121127 10.1016/j.biomaterials.2021.121127 34564034
9. GBD 2019 Fracture Collaborators Global, regional, and national burden of bone fractures in 204 countries and territories, 1990–2019: A systematic analysis from the Global Burden of Disease Study 2019 Lancet Healthy Longev. 2021 2 e580 e592 10.1016/S2666-7568(21)00172-0 34723233 PMC8547262
10. Coury F. Peyruchaud O. Machuca-Gayet I. Osteoimmunology of Bone Loss in Inflammatory Rheumatic Diseases Front. Immunol. 2019 10 679 10.3389/fimmu.2019.00679 31001277 PMC6456657
11. Lukac N. Katavic V. Novak S. Sucur A. Filipovic M. Kalajzic I. Grcevic D. Kovacic N. What do we know about bone morphogenetic proteins and osteochondroprogenitors in inflammatory conditions? Bone 2020 137 115403 10.1016/j.bone.2020.115403 32371019
12. Gravallese E.M. Firestein G.S. Rheumatoid Arthritis—Common Origins, Divergent Mechanisms N. Engl. J. Med. 2023 388 529 542 10.1056/NEJMra2103726 36780677
13. Zhou M. Graves D.T. Impact of the host response and osteoblast lineage cells on periodontal disease Front. Immunol. 2022 13 998244 10.3389/fimmu.2022.998244 36304447 PMC9592920
14. Raggatt L.J. Partridge N.C. Cellular and molecular mechanisms of bone remodeling J. Biol. Chem. 2010 285 25103 25108 10.1074/jbc.R109.041087 20501658 PMC2919071
15. Weivoda M.M. Bradley E.W. Macrophages and Bone Remodeling J. Bone Miner. Res. 2023 38 359 369 10.1002/jbmr.4773 36651575 PMC10023335
16. Boyle W.J. Simonet W.S. Lacey D.L. Osteoclast differentiation and activation Nature 2003 423 337 342 10.1038/nature01658 12748652
17. Wan Y. Nemoto Y.L. Oikawa T. Takano K. Fujiwara T.K. Tsujita K. Itoh T. Mechanical control of osteoclast fusion by membrane-cortex attachment and BAR proteins J. Cell. Biol. 2025 224 e202411024 10.1083/jcb.202411024 40338171 PMC12060795
18. Kim J.H. Kim N. Signaling Pathways in Osteoclast Differentiation Chonnam Med. J. 2016 52 12 17 10.4068/cmj.2016.52.1.12 26865996 PMC4742606
19. Neve A. Corrado A. Cantatore F.P. Osteoblast physiology in normal and pathological conditions Cell Tissue Res. 2011 343 289 302 10.1007/s00441-010-1086-1 21120535
20. Bonewald L.F. The amazing osteocyte J. Bone Miner. Res. 2011 26 229 238 10.1002/jbmr.320 21254230 PMC3179345
21. Kenkre J.S. Bassett J. The bone remodelling cycle Ann. Clin. Biochem. 2018 55 308 327 10.1177/0004563218759371 29368538
22. Delaisse J.M. The reversal phase of the bone-remodeling cycle: Cellular prerequisites for coupling resorption and formation Bonekey Rep. 2014 3 561 10.1038/bonekey.2014.56 25120911 PMC4130129
23. McDonald M.M. Khoo W.H. Ng P.Y. Xiao Y. Zamerli J. Thatcher P. Kyaw W. Pathmanandavel K. Grootveld A.K. Moran I. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption Cell 2021 184 1330 1347 e13 10.1016/j.cell.2021.02.002 33636130 PMC7938889
24. Chang M.K. Raggatt L.J. Alexander K.A. Kuliwaba J.S. Fazzalari N.L. Schroder K. Maylin E.R. Ripoll V.M. Hume D.A. Pettit A.R. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo J. Immunol. 2008 181 1232 1244 10.4049/jimmunol.181.2.1232 18606677
25. Austyn J.M. Gordon S. F4/80, a monoclonal antibody directed specifically against the mouse macrophage Eur. J. Immunol. 1981 11 805 815 10.1002/eji.1830111013 7308288
26. Lean J.M. Matsuo K. Fox S.W. Fuller K. Gibson F.M. Draycott G. Wani M.R. Bayley K.E. Wong B.R. Choi Y. Osteoclast lineage commitment of bone marrow precursors through expression of membrane-bound TRANCE Bone 2000 27 29 40 10.1016/S8756-3282(00)00306-9 10865206
27. Vasconcelos D.P. Costa M. Amaral I.F. Barbosa M.A. Aguas A.P. Barbosa J.N. Modulation of the inflammatory response to chitosan through M2 macrophage polarization using pro-resolution mediators Biomaterials 2015 37 116 123 10.1016/j.biomaterials.2014.10.035 25453942
28. Ballet J.J. Griscelli C. Coutris C. Milhaud G. Maroteaux P. Bone-marrow transplantation in osteopetrosis Lancet 1977 2 1137 10.1016/S0140-6736(77)90592-X 73050
29. Coccia P.F. Krivit W. Cervenka J. Clawson C. Kersey J.H. Kim T.H. Nesbit M.E. Ramsay N.K. Warkentin P.I. Teitelbaum S.L. Successful bone-marrow transplantation for infantile malignant osteopetrosis N. Engl. J. Med. 1980 302 701 708 10.1056/NEJM198003273021301 6986555
30. Sorell M. Kapoor N. Kirkpatrick D. Rosen J.F. Chaganti R.S. Lopez C. Dupont B. Pollack M.S. Terrin B.N. Harris M.B. Marrow transplantation for juvenile osteopetrosis Am. J. Med. 1981 70 1280 1287 10.1016/0002-9343(81)90839-1 7015858
31. Ash P. Loutit J.F. Townsend K.M. Osteoclasts derived from haematopoietic stem cells Nature 1980 283 669 670 10.1038/283669a0 7354855
32. Frattini A. Blair H.C. Sacco M.G. Cerisoli F. Faggioli F. Cato E.M. Pangrazio A. Musio A. Rucci F. Sobacchi C. Rescue of ATPa3-deficient murine malignant osteopetrosis by hematopoietic stem cell transplantation in utero Proc. Natl. Acad. Sci. USA 2005 102 14629 14634 10.1073/pnas.0507637102 16195375 PMC1253616
33. Walker D.G. Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells Science 1975 190 784 785 10.1126/science.1105786 1105786
34. Jacome-Galarza C.E. Percin G.I. Muller J.T. Mass E. Lazarov T. Eitler J. Rauner M. Yadav V.K. Crozet L. Bohm M. Developmental origin, functional maintenance and genetic rescue of osteoclasts Nature 2019 568 541 545 10.1038/s41586-019-1105-7 30971820 PMC6910203
35. Xiang Q. Li L. Ji W. Gawlitta D. Walboomers X.F. van den Beucken J. Beyond resorption: Osteoclasts as drivers of bone formation Cell Regen. 2024 13 22 10.1186/s13619-024-00205-x 39392536 PMC11469995
36. Yahara Y. Barrientos T. Tang Y.J. Puviindran V. Nadesan P. Zhang H. Gibson J.R. Gregory S.G. Diao Y. Xiang Y. Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair Nat. Cell Biol. 2020 22 49 59 10.1038/s41556-019-0437-8 31907410 PMC6953622
37. Yahara Y. Ma X. Gracia L. Alman B.A. Monocyte/Macrophage Lineage Cells From Fetal Erythromyeloid Progenitors Orchestrate Bone Remodeling and Repair Front. Cell Dev. Biol. 2021 9 622035 10.3389/fcell.2021.622035 33614650 PMC7889961
38. Yahara Y. Nguyen T. Ishikawa K. Kamei K. Alman B.A. The origins and roles of osteoclasts in bone development, homeostasis and repair Development 2022 149 dev199908 10.1242/dev.199908 35502779 PMC9124578
39. Novak S. Roeder E. Kalinowski J. Jastrzebski S. Aguila H.L. Lee S.K. Kalajzic I. Lorenzo J.A. Osteoclasts Derive Predominantly from Bone Marrow-Resident CX3CR1(+) Precursor Cells in Homeostasis, whereas Circulating CX3CR1(+) Cells Contribute to Osteoclast Development during Fracture Repair J. Immunol. 2020 204 868 878 10.4049/jimmunol.1900665 31915261 PMC7002248
40. Alle Q. Le Borgne E. Bensadoun P. Lemey C. Bechir N. Gabanou M. Estermann F. Bertrand-Gaday C. Pessemesse L. Toupet K. A single short reprogramming early in life initiates and propagates an epigenetically related mechanism improving fitness and promoting an increased healthy lifespan Aging Cell 2022 21 e13714 10.1111/acel.13714 36251933 PMC9649606
41. Macip C.C. Hasan R. Hoznek V. Kim J. Lu Y.R. Metzger LEt Sethna S. Davidsohn N. Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice Cell. Reprogram. 2024 26 24 32 10.1089/cell.2023.0072 38381405 PMC10909732
42. Pessina P. Di Stefano B. Early Life Reprogramming-Based Treatment Promotes Longevity Cell. Reprogram. 2023 25 9 10 10.1089/cell.2022.0153 36594927 PMC9963505
43. Root S.H. Aguila H.L. Novel population of human monocyte and osteoclast progenitors from pluripotent stem cells and peripheral blood Blood Adv. 2021 5 4435 4446 10.1182/bloodadvances.2021004552 34581760 PMC8579260
44. Flanagan A.M. Massey H.M. Generating human osteoclasts in vitro from bone marrow and peripheral blood Methods Mol. Med. 2003 80 113 128 10.1385/1-59259-366-6:113 12728714
45. Jacquin C. Gran D.E. Lee S.K. Lorenzo J.A. Aguila H.L. Identification of multiple osteoclast precursor populations in murine bone marrow J. Bone Miner. Res. 2006 21 67 77 10.1359/JBMR.051007 16355275
46. Takahashi N. Kukita T. MacDonald B.R. Bird A. Mundy G.R. McManus L.M. Miller M. Boyde A. Jones S.J. Roodman G.D. Osteoclast-like cells form in long-term human bone marrow but not in peripheral blood cultures J. Clin. Investig. 1989 83 543 550 10.1172/JCI113916 2783589 PMC303713
47. Xiao Y. Zijl S. Wang L. de Groot D.C. van Tol M.J. Lankester A.C. Borst J. Identification of the Common Origins of Osteoclasts, Macrophages, and Dendritic Cells in Human Hematopoiesis Stem Cell Rep. 2015 4 984 994 10.1016/j.stemcr.2015.04.012 26004632 PMC4471835
48. Mbalaviele G. Jaiswal N. Meng A. Cheng L. Van Den Bos C. Thiede M. Human mesenchymal stem cells promote human osteoclast differentiation from CD34+ bone marrow hematopoietic progenitors Endocrinology 1999 140 3736 3743 10.1210/endo.140.8.6880 10433234
49. Inoue K. Qin Y. Xia Y. Han J. Yuan R. Sun J. Xu R. Jiang J.X. Greenblatt M.B. Zhao B. Bone marrow Adipoq-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis, and bone mass eLife 2023 12 e82118 10.7554/eLife.82118 36779851 PMC10005769
50. Lu J. He Q. Wang H. Yao L. Duffy M. Guo H. Braun C. Zhou Y. Liang Q. Lin Y. Bone marrow adipogenic lineage precursors are the major regulator of bone resorption in adult mice Bone Res. 2025 13 39 10.1038/s41413-025-00405-4 40102423 PMC11920254
51. Qin L. Lu J. He Q. Wang H. Yao L. Duffy M. Guo H. Braun C. Lin Y. Zhou Y. Bone marrow adipogenic lineage precursors are the major regulator of bone resorption in adult mice Res Sq. 2024 10.21203/rs.3.rs-4809633/v1 40102423 PMC11920254
52. Zhong L. Lu J. Fang J. Yao L. Yu W. Gui T. Duffy M. Holdreith N. Bautista C.A. Huang X. Csf1 from marrow adipogenic precursors is required for osteoclast formation and hematopoiesis in bone eLife 2023 12 e82112 10.7554/eLife.82112 36779854 PMC10005765
53. Flegar D. Filipovic M. Sucur A. Markotic A. Lukac N. Sisl D. Ikic Matijasevic M. Jajic Z. Kelava T. Katavic V. Preventive CCL2/CCR2 Axis Blockade Suppresses Osteoclast Activity in a Mouse Model of Rheumatoid Arthritis by Reducing Homing of CCR2(hi) Osteoclast Progenitors to the Affected Bone Front. Immunol. 2021 12 767231 10.3389/fimmu.2021.767231 34925336 PMC8677701
54. Petitprez V. Royer B. Desoutter J. Guiheneuf E. Rigolle A. Marolleau J.P. Kamel S. Guillaume N. CD14+ CD16+ monocytes rather than CD14+ CD51/61+ monocytes are a potential cytological marker of circulating osteoclast precursors in multiple myeloma. A preliminary study Int. J. Lab. Hematol. 2015 37 29 35 10.1111/ijlh.12216 24661393
55. Sorensen M.G. Henriksen K. Schaller S. Henriksen D.B. Nielsen F.C. Dziegiel M.H. Karsdal M.A. Characterization of osteoclasts derived from CD14+ monocytes isolated from peripheral blood J. Bone Miner. Metab. 2007 25 36 45 10.1007/s00774-006-0725-9 17187192
56. Xue J. Xu L. Zhu H. Bai M. Li X. Zhao Z. Zhong H. Cheng G. Li X. Hu F. CD14(+)CD16(-) monocytes are the main precursors of osteoclasts in rheumatoid arthritis via expressing Tyro3TK Arthritis Res. Ther. 2020 22 221 10.1186/s13075-020-02308-7 32958023 PMC7507256
57. Sawant A. Deshane J. Jules J. Lee C.M. Harris B.A. Feng X. Ponnazhagan S. Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer Cancer Res. 2013 73 672 682 10.1158/0008-5472.CAN-12-2202 23243021 PMC3548966
58. Ishii M. Kikuta J. Shimazu Y. Meier-Schellersheim M. Germain R.N. Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo J. Exp. Med. 2010 207 2793 2798 10.1084/jem.20101474 21135136 PMC3005230
59. Jacome-Galarza C.E. Lee S.K. Lorenzo J.A. Aguila H.L. Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery J. Bone Miner. Res. 2013 28 1203 1213 10.1002/jbmr.1822 23165930 PMC3625454
60. Lee M.Y. Lottsfeldt J.L. Fevold K.L. Identification and characterization of osteoclast progenitors by clonal analysis of hematopoietic cells Blood 1992 80 1710 1716 10.1182/blood.V80.7.1710.1710 1391940
61. Nakamichi Y. Mizoguchi T. Arai A. Kobayashi Y. Sato M. Penninger J.M. Yasuda H. Kato S. DeLuca H.F. Suda T. Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice Proc. Natl. Acad. Sci. USA 2012 109 10006 10011 10.1073/pnas.1207361109 22670054 PMC3382519
62. Kotani M. Kikuta J. Klauschen F. Chino T. Kobayashi Y. Yasuda H. Tamai K. Miyawaki A. Kanagawa O. Tomura M. Systemic circulation and bone recruitment of osteoclast precursors tracked by using fluorescent imaging techniques J. Immunol. 2013 190 605 612 10.4049/jimmunol.1201345 23241888
63. Jansen I.D. Vermeer J.A. Bloemen V. Stap J. Everts V. Osteoclast fusion and fission Calcif. Tissue Int. 2012 90 515 522 10.1007/s00223-012-9600-y 22527205 PMC3349023
64. Mohamad S.F. Gunawan A. Blosser R. Childress P. Aguilar-Perez A. Ghosh J. Hong J.M. Liu J. Kanagasabapathy D. Kacena M.A. Neonatal Osteomacs and Bone Marrow Macrophages Differ in Phenotypic Marker Expression and Function J. Bone Miner. Res. 2021 36 1580 1593 10.1002/jbmr.4314 33900648 PMC10229197
65. Miron R.J. Bosshardt D.D. OsteoMacs: Key players around bone biomaterials Biomaterials 2016 82 1 19 10.1016/j.biomaterials.2015.12.017 26735169
66. Cho S.W. Soki F.N. Koh A.J. Eber M.R. Entezami P. Park S.I. van Rooijen N. McCauley L.K. Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone Proc. Natl. Acad. Sci. USA 2014 111 1545 1550 10.1073/pnas.1315153111 24406853 PMC3910564
67. Batoon L. Millard S.M. Raggatt L.J. Wu A.C. Kaur S. Sun L.W.H. Williams K. Sandrock C. Ng P.Y. Irvine K.M. Osteal macrophages support osteoclast-mediated resorption and contribute to bone pathology in a postmenopausal osteoporosis mouse model J. Bone Miner. Res. 2021 36 2214 2228 10.1002/jbmr.4413 34278602
68. Alexander K.A. Chang M.K. Maylin E.R. Kohler T. Muller R. Wu A.C. Van Rooijen N. Sweet M.J. Hume D.A. Raggatt L.J. Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model J. Bone Miner. Res. 2011 26 1517 1532 10.1002/jbmr.354 21305607
69. Bravo-Jaimes K. Walton B. Tung P. Smalling R.W. An Unusual Cause of Hypoxia: Ventricular Septal Defect, Pulmonary Artery Atresia, and Major Aortopulmonary Collaterals Diagnosed in the Adult Cardiac Catheterization Lab Case Rep. Cardiol. 2020 2020 4726529 10.1155/2020/4726529 32047673 PMC7007747
70. Taylor R.T. Patel S.R. Lin E. Butler B.R. Lake J.G. Newberry R.D. Williams I.R. Lymphotoxin-independent expression of TNF-related activation-induced cytokine by stromal cells in cryptopatches, isolated lymphoid follicles, and Peyer’s patches J. Immunol. 2007 178 5659 5667 10.4049/jimmunol.178.9.5659 17442949
71. Sigl V. Jones L.P. Penninger J.M. RANKL/RANK: From bone loss to the prevention of breast cancer Open Biol. 2016 6 10.1098/rsob.160230 27881737 PMC5133443
72. Renema N. Navet B. Heymann M.F. Lezot F. Heymann D. RANK-RANKL signalling in cancer Biosci Rep. 2016 36 160230 10.1042/BSR20160150 27279652 PMC4974605
73. Katavic V. Grcevic D. Lee S.K. Kalinowski J. Jastrzebski S. Dougall W. Anderson D. Puddington L. Aguila H.L. Lorenzo J.A. The surface antigen CD45R identifies a population of estrogen-regulated murine marrow cells that contain osteoclast precursors Bone 2003 32 581 590 10.1016/S8756-3282(03)00097-8 12810165
74. Charles J.F. Hsu L.Y. Niemi E.C. Weiss A. Aliprantis A.O. Nakamura M.C. Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function J. Clin. Investig. 2012 122 4592 4605 10.1172/JCI60920 23114597 PMC3533532
75. Cai X. Li Z. Zhao Y. Katz J. Michalek S.M. Feng X. Li Y. Zhang P. Enhanced dual function of osteoclast precursors following calvarial Porphyromonas gingivalis infection J. Periodontal Res. 2020 55 410 425 10.1111/jre.12725 31944305 PMC7250733
76. Zhou J. Tang Z. Gao S. Li C. Feng Y. Zhou X. Tumor-Associated Macrophages: Recent Insights and Therapies Front. Oncol. 2020 10 188 10.3389/fonc.2020.00188 32161718 PMC7052362
77. Ikic Matijasevic M. Flegar D. Kovacic N. Katavic V. Kelava T. Sucur A. Ivcevic S. Cvija H. Lazic Mosler E. Kalajzic I. Increased chemotaxis and activity of circulatory myeloid progenitor cells may contribute to enhanced osteoclastogenesis and bone loss in the C57BL/6 mouse model of collagen-induced arthritis Clin. Exp. Immunol. 2016 186 321 335 10.1111/cei.12862 27612450 PMC5108074
78. Kleinnijenhuis J. Quintin J. Preijers F. Joosten L.A. Ifrim D.C. Saeed S. Jacobs C. van Loenhout J. de Jong D. Stunnenberg H.G. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes Proc. Natl. Acad. Sci. USA 2012 109 17537 17542 10.1073/pnas.1202870109 22988082 PMC3491454
79. Saeed S. Quintin J. Kerstens H.H. Rao N.A. Aghajanirefah A. Matarese F. Cheng S.C. Ratter J. Berentsen K. van der Ent M.A. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity Science 2014 345 1251086 10.1126/science.1251086 25258085 PMC4242194
80. Moerings B.G.J. de Graaff P. Furber M. Witkamp R.F. Debets R. Mes J.J. van Bergenhenegouwen J. Govers C. Continuous Exposure to Non-Soluble beta-Glucans Induces Trained Immunity in M-CSF-Differentiated Macrophages Front. Immunol. 2021 12 672796 10.3389/fimmu.2021.672796 34149707 PMC8208035
81. Arai F. Miyamoto T. Ohneda O. Inada T. Sudo T. Brasel K. Miyata T. Anderson D.M. Suda T. Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors J. Exp. Med. 1999 190 1741 1754 10.1084/jem.190.12.1741 10601350 PMC2195707
82. Miyamoto T. Arai F. Ohneda O. Takagi K. Anderson D.M. Suda T. An adherent condition is required for formation of multinuclear osteoclasts in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor kappa B ligand Blood 2000 96 4335 4343 10.1182/blood.V96.13.4335 11110710
83. Mizoguchi T. Muto A. Udagawa N. Arai A. Yamashita T. Hosoya A. Ninomiya T. Nakamura H. Yamamoto Y. Kinugawa S. Identification of cell cycle-arrested quiescent osteoclast precursors in vivo J. Cell Biol. 2009 184 541 554 10.1083/jcb.200806139 19237598 PMC2654120
84. Puchner A. Saferding V. Bonelli M. Mikami Y. Hofmann M. Brunner J.S. Caldera M. Goncalves-Alves E. Binder N.B. Fischer A. Non-classical monocytes as mediators of tissue destruction in arthritis Ann. Rheum. Dis. 2018 77 1490 1497 10.1136/annrheumdis-2018-213250 29959183 PMC6161666
85. Miyamoto T. Regulators of osteoclast differentiation and cell-cell fusion Keio J. Med. 2011 60 101 105 10.2302/kjm.60.101 22200633
86. Muguruma Y. Lee M.Y. Isolation and characterization of murine clonogenic osteoclast progenitors by cell surface phenotype analysis Blood 1998 91 1272 1279 10.1182/blood.V91.4.1272 9454757
87. Xiao Y. Palomero J. Grabowska J. Wang L. de Rink I. van Helvert L. Borst J. Macrophages and osteoclasts stem from a bipotent progenitor downstream of a macrophage/osteoclast/dendritic cell progenitor Blood Adv. 2017 1 1993 2006 10.1182/bloodadvances.2017008540 29296846 PMC5728283
88. Beerman I. Maloney W.J. Weissmann I.L. Rossi D.J. Stem cells and the aging hematopoietic system Curr. Opin. Immunol. 2010 22 500 506 10.1016/j.coi.2010.06.007 20650622 PMC5817978
89. Jevon M. Sabokbar A. Fujikawa Y. Hirayama T. Neale S.D. Wass J. Athanasou N.A. Gender- and age-related differences in osteoclast formation from circulating precursors J. Endocrinol. 2002 172 673 681 10.1677/joe.0.1720673 11874715
90. Kim H.N. Chang J. Iyer S. Han L. Campisi J. Manolagas S.C. Zhou D. Almeida M. Elimination of senescent osteoclast progenitors has no effect on the age-associated loss of bone mass in mice Aging Cell 2019 18 e12923 10.1111/acel.12923 30773784 PMC6516158
91. Koshihara Y. Suematsu A. Feng D. Okawara R. Ishibashi H. Yamamoto S. Osteoclastogenic potential of bone marrow cells increases with age in elderly women with fracture Mech. Ageing Dev. 2002 123 1321 1331 10.1016/S0047-6374(02)00071-4 12297335
92. Moller A.M.J. Delaisse J.M. Olesen J.B. Madsen J.S. Canto L.M. Bechmann T. Rogatto S.R. Soe K. Aging and menopause reprogram osteoclast precursors for aggressive bone resorption Bone Res. 2020 8 27 10.1038/s41413-020-0102-7 32637185 PMC7329827
93. Collins F.L. Stone M.D. Turton J. McCabe L.R. Wang E.C.Y. Williams A.S. Oestrogen-deficiency induces bone loss by modulating CD14(+) monocyte and CD4(+) T cell DR3 expression and serum TL1A levels BMC Musculoskelet. Disord. 2019 20 326 10.1186/s12891-019-2704-z 31299941 PMC6626337
94. Kaneko K. Tsai J. Menez D. Oh B. Suh A.J. Bae S. Mizuno M. Umemoto A. Giannopoulou E. Fujii T. Cellular signatures in human blood track bone mineral density in postmenopausal women JCI Insight 2024 9 e178977 10.1172/jci.insight.178977 39576015 PMC11601907
95. Clowes J.A. Eghbali-Fatourechi G.Z. McCready L. Oursler M.J. Khosla S. Riggs B.L. Estrogen action on bone marrow osteoclast lineage cells of postmenopausal women in vivo Osteoporos. Int. 2009 20 761 769 10.1007/s00198-008-0731-y 18769961 PMC2842571
96. Kirkwood K.L. Zhang L. Thiyagarajan R. Seldeen K.L. Troen B.R. Myeloid-Derived Suppressor Cells at the Intersection of Inflammaging and Bone Fragility Immunol. Investig. 2018 47 844 854 10.1080/08820139.2018.1552360 31282803 PMC7039312
97. Salas A. Ponnusamy S. Senkal C.E. Meyers-Needham M. Selvam S.P. Saddoughi S.A. Apohan E. Sentelle R.D. Smith C. Gault C.R. Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A Blood 2011 117 5941 5952 10.1182/blood-2010-08-300772 21527515 PMC3112039
98. Thiyagarajan R. Zhang L. Glover O.D. Kwack K.H. Ahmed S. Murray E. Yellapu N.K. Bard J. Seldeen K.L. Rosario S.R. Age-related increase of CD38 directs osteoclastogenic potential of monocytic myeloid-derived suppressor cells through mitochondrial dysfunction in male mice Aging Cell 2024 23 e14298 10.1111/acel.14298 39180173 PMC11561650
99. Perkins S.L. Gibbons R. Kling S. Kahn A.J. Age-related bone loss in mice is associated with an increased osteoclast progenitor pool Bone 1994 15 65 72 10.1016/8756-3282(94)90893-1 8024854
100. Cao J.J. Wronski T.J. Iwaniec U. Phleger L. Kurimoto P. Boudignon B. Halloran B.P. Aging increases stromal/osteoblastic cell-induced osteoclastogenesis and alters the osteoclast precursor pool in the mouse J. Bone Miner. Res. 2005 20 1659 1668 10.1359/JBMR.050503 16059637
101. Ambrosi T.H. Marecic O. McArdle A. Sinha R. Gulati G.S. Tong X. Wang Y. Steininger H.M. Hoover M.Y. Koepke L.S. Aged skeletal stem cells generate an inflammatory degenerative niche Nature 2021 597 256 262 10.1038/s41586-021-03795-7 34381212 PMC8721524
102. Schell H. Lienau J. Epari D.R. Seebeck P. Exner C. Muchow S. Bragulla H. Haas N.P. Duda G.N. Osteoclastic activity begins early and increases over the course of bone healing Bone 2006 38 547 554 10.1016/j.bone.2005.09.018 16326155
103. Takeyama K. Chatani M. Takano Y. Kudo A. In-vivo imaging of the fracture healing in medaka revealed two types of osteoclasts before and after the callus formation by osteoblasts Dev. Biol. 2014 394 292 304 10.1016/j.ydbio.2014.08.007 25131195
104. Geurtzen K. Lopez-Delgado A.C. Duseja A. Kurzyukova A. Knopf F. Laser-mediated osteoblast ablation triggers a pro-osteogenic inflammatory response regulated by reactive oxygen species and glucocorticoid signaling in zebrafish Development 2022 149 dev199803 10.1242/dev.199803 35485304
105. Xie H. Cui Z. Wang L. Xia Z. Hu Y. Xian L. Li C. Xie L. Crane J. Wan M. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis Nat. Med. 2014 20 1270 1278 10.1038/nm.3668 25282358 PMC4224644
106. Walia B. Lingenheld E. Duong L. Sanjay A. Drissi H. A novel role for cathepsin K in periosteal osteoclast precursors during fracture repair Ann. N. Y. Acad. Sci. 2018 1415 57 68 10.1111/nyas.13629 29479711
107. Riquelme-Guzman C. Tsai S.L. Carreon Paz K. Nguyen C. Oriola D. Schuez M. Brugues J. Currie J.D. Sandoval-Guzman T. Osteoclast-mediated resorption primes the skeleton for successful integration during axolotl limb regeneration Elife 2022 11 e79966 10.7554/eLife.79966 36218256 PMC9581535
108. Biguetti C.C. Cavalla F. Silveira E.M. Fonseca A.C. Vieira A.E. Tabanez A.P. Rodrigues D.C. Trombone A.P.F. Garlet G.P. Oral implant osseointegration model in C57Bl/6 mice: Microtomographic, histological, histomorphometric and molecular characterization J. Appl. Oral Sci. 2018 26 e20170601 10.1590/1678-7757-2017-0601 29898187 PMC5963915
109. Futami T. Fujii N. Ohnishi H. Taguchi N. Kusakari H. Ohshima H. Maeda T. Tissue response to titanium implants in the rat maxilla: Ultrastructural and histochemical observations of the bone-titanium interface J. Periodontol. 2000 71 287 298 10.1902/jop.2000.71.2.287 10711620
110. Lenneras M. Palmquist A. Norlindh B. Emanuelsson L. Thomsen P. Omar O. Oxidized Titanium Implants Enhance Osseointegration via Mechanisms Involving RANK/RANKL/OPG Regulation Clin. Implant. Dent. Relat. Res. 2015 17 (Suppl. 2) e486 e500 10.1111/cid.12276 25536123
111. Makishi S. Watanabe T. Saito K. Ohshima H. Effect of Hydroxyapatite/beta-Tricalcium Phosphate on Osseointegration after Implantation into Mouse Maxilla Int. J. Mol. Sci. 2023 24 3124 10.3390/ijms24043124 36834535 PMC9965049
112. Shirakura M. Fujii N. Ohnishi H. Taguchi Y. Ohshima H. Nomura S. Maeda T. Tissue response to titanium implantation in the rat maxilla, with special reference to the effects of surface conditions on bone formation Clin. Oral. Implant. Res. 2003 14 687 696 10.1046/j.0905-7161.2003.00960.x 15015943
113. Slaets E. Carmeliet G. Naert I. Duyck J. Early cellular responses in cortical bone healing around unloaded titanium implants: An animal study J. Periodontol. 2006 77 1015 1024 10.1902/jop.2006.050196 16734577
114. Childs L.M. Paschalis E.P. Xing L. Dougall W.C. Anderson D. Boskey A.L. Puzas J.E. Rosier R.N. O’Keefe R.J. Boyce B.F. In vivo RANK signaling blockade using the receptor activator of NF-kappaB:Fc effectively prevents and ameliorates wear debris-induced osteolysis via osteoclast depletion without inhibiting osteogenesis J. Bone Miner. Res. 2002 17 192 199 10.1359/jbmr.2002.17.2.192 11811549
115. Zhang L. Jia T.H. Chong A.C. Bai L. Yu H. Gong W. Wooley P.H. Yang S.Y. Cell-based osteoprotegerin therapy for debris-induced aseptic prosthetic loosening on a murine model Gene Ther. 2010 17 1262 1269 10.1038/gt.2010.64 20428210 PMC2914841
116. Agemura T. Hasegawa T. Yari S. Kikuta J. Ishii M. Arthritis-associated osteoclastogenic macrophages (AtoMs) participate in pathological bone erosion in rheumatoid arthritis Immunol. Med. 2022 45 22 26 10.1080/25785826.2021.1944547 34187325
117. Hasegawa T. Updating the pathophysiology of arthritic bone destruction: Identifying and visualizing pathological osteoclasts in pannus Immunol. Med. 2021 44 246 251 10.1080/25785826.2021.1913883 34010590
118. Hasegawa T. Kikuta J. Sudo T. Matsuura Y. Matsui T. Simmons S. Ebina K. Hirao M. Okuzaki D. Yoshida Y. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1 Nat Immunol. 2019 20 1631 1643 10.1038/s41590-019-0526-7 31740799
119. Filipovic M. Flegar D. Anicic S. Sisl D. Kelava T. Kovacic N. Sucur A. Grcevic D. Transcriptome profiling of osteoclast subsets associated with arthritis: A pathogenic role of CCR2(hi) osteoclast progenitors Front. Immunol. 2022 13 994035 10.3389/fimmu.2022.994035 36591261 PMC9797520
120. Sucur A. Jajic Z. Artukovic M. Matijasevic M.I. Anic B. Flegar D. Markotic A. Kelava T. Ivcevic S. Kovacic N. Chemokine signals are crucial for enhanced homing and differentiation of circulating osteoclast progenitor cells Arthritis Res. Ther. 2017 19 142 10.1186/s13075-017-1337-6 28619088 PMC5472975
121. Yao Z. Li P. Zhang Q. Schwarz E.M. Keng P. Arbini A. Boyce B.F. Xing L. Tumor necrosis factor-alpha increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-Fms expression J. Biol. Chem. 2006 281 11846 11855 10.1074/jbc.M512624200 16461346
122. Xia Y. Inoue K. Du Y. Baker S.J. Premkumar Reddy E. Greenblatt M.B. Zhao B. TGFbeta reprograms TNF stimulation of macrophages towards a non-canonical pathway driving inflammatory osteoclastogenesis Nat. Commun. 2022 13 3920 10.1038/s41467-022-31475-1 35798734 PMC9263175
123. Zhao Y. Li Z. Su L. Ballesteros-Tato A. Katz J. Michalek S.M. Feng X. Zhang P. Frontline Science: Characterization and regulation of osteoclast precursors following chronic Porphyromonas gingivalis infection J. Leukoc. Biol. 2020 108 1037 1050 10.1002/JLB.1HI0620-230R 33463750
124. Kurtis B. Tuter G. Serdar M. Akdemir P. Uygur C. Firatli E. Bal B. Gingival crevicular fluid levels of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha in patients with chronic and aggressive periodontitis J. Periodontol. 2005 76 1849 1855 10.1902/jop.2005.76.11.1849 16274303
125. de Vries T.J. El Bakkali I. Kamradt T. Schett G. Jansen I.D.C. D’Amelio P. What Are the Peripheral Blood Determinants for Increased Osteoclast Formation in the Various Inflammatory Diseases Associated with Bone Loss? Front. Immunol. 2019 10 505 10.3389/fimmu.2019.00505 30941138 PMC6434996
126. Durstberger G. Nguyen P.Q. Hohensinner V. Pietschmann P. Rausch-Fan X. Andrukhov O. Effect of Enamel Matrix Derivatives on Osteoclast Formation from PBMC of Periodontitis Patients and Healthy Individuals after Interaction with Activated Endothelial Cells Medicina 2021 57 269 10.3390/medicina57030269 33804249 PMC7998895
127. Herrera B.S. Bastos A.S. Coimbra L.S. Teixeira S.A. Rossa C. Van Dyke T.E. Jr. Muscara M.N. Spolidorio L.C. Peripheral blood mononuclear phagocytes from patients with chronic periodontitis are primed for osteoclast formation J. Periodontol. 2014 85 e72 e81 10.1902/jop.2013.130280 24059638
128. Kumar A. Mahendra J. Samuel S. Govindraj J. Loganathan T. Vashum Y. Mahendra L. Krishnamoorthy T. Platelet-rich fibrin/biphasic calcium phosphate impairs osteoclast differentiation and promotes apoptosis by the intrinsic mitochondrial pathway in chronic periodontitis J. Periodontol. 2019 90 61 71 10.1002/JPER.17-0306 29958327
129. Tjoa S.T. de Vries T.J. Schoenmaker T. Kelder A. Loos B.G. Everts V. Formation of osteoclast-like cells from peripheral blood of periodontitis patients occurs without supplementation of macrophage colony-stimulating factor J. Clin. Periodontol. 2008 35 568 575 10.1111/j.1600-051X.2008.01241.x 18435789
130. Rahmani N.R. Belluomo R. Kruyt M.C. Gawlitta D. Joosten L.A.B. Weinans H. Croes M. Trained innate immunity modulates osteoblast and osteoclast differentiation Stem Cell Rev. Rep. 2024 20 1121 1134 10.1007/s12015-024-10711-9 38478316 PMC11087362
131. Meirow Y. Jovanovic M. Zur Y. Habib J. Colombo D.F. Twaik N. Ashkenazi-Preiser H. Ben-Meir K. Mikula I. Jr Reuven O. Specific inflammatory osteoclast precursors induced during chronic inflammation give rise to highly active osteoclasts associated with inflammatory bone loss Bone Res. 2022 10 36 10.1038/s41413-022-00206-z 35396510 PMC8993801
132. Fanucchi S. Dominguez-Andres J. Joosten L.A.B. Netea M.G. Mhlanga M.M. The Intersection of Epigenetics and Metabolism in Trained Immunity Immunity 2021 54 32 43 10.1016/j.immuni.2020.10.011 33220235
133. Karsdal M.A. Leeming D.J. Dam E.B. Henriksen K. Alexandersen P. Pastoureau P. Altman R.D. Christiansen C. Should subchondral bone turnover be targeted when treating osteoarthritis? Osteoarthr. Cartil. 2008 16 638 646 10.1016/j.joca.2008.01.014 18362080
134. Siebelt M. Waarsing J.H. Groen H.C. Muller C. Koelewijn S.J. de Blois E. Verhaar J.A. de Jong M. Weinans H. Inhibited osteoclastic bone resorption through alendronate treatment in rats reduces severe osteoarthritis progression Bone 2014 66 163 170 10.1016/j.bone.2014.06.009 24933343
135. Su W. Liu G. Liu X. Zhou Y. Sun Q. Zhen G. Wang X. Hu Y. Gao P. Demehri S. Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development JCI Insight 2020 5 e135446 10.1172/jci.insight.135446 32208385 PMC7205438
136. Walsh D.A. McWilliams D.F. Turley M.J. Dixon M.R. Franses R.E. Mapp P.I. Wilson D. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis Rheumatology 2010 49 1852 1861 10.1093/rheumatology/keq188 20581375 PMC2936950
137. Zhang H. Wang L. Cui J. Wang S. Han Y. Shao H. Wang C. Hu Y. Li X. Zhou Q. Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression Sci. Adv. 2023 9 eabo7868 10.1126/sciadv.abo7868 37018403 PMC10075992
138. Zhu S. Zhu J. Zhen G. Hu Y. An S. Li Y. Zheng Q. Chen Z. Yang Y. Wan M. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain J. Clin. Investig. 2019 129 1076 1093 10.1172/JCI121561 30530994 PMC6391093