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Substance P Exacerbates the Inflammatory and Pro-osteoclastogenic Responses of Murine Osteoclasts and Osteoblasts to Staphylococcus aureus.

Staphylococcus aureus infections of bone tissue are associated with inflammatory bone loss. Resident bone cells, including osteoblasts and osteoclasts, can perceive S. aureus and produce an array of inflammatory and pro-osteoclastogenic mediators, thereby contributing to such damage. The neuropeptide substance P (SP) has been shown to exacerbate microbially induced inflammation at sites such as the gut and the brain and has previously been shown to affect bone cell differentiation and activity. Here we demonstrate that the interaction of SP with its high affinity receptor, neurokinin-1 recepto…

Orthogonal targeting of osteoclasts and myeloma cells for radionuclide stimulated dynamic therapy induces multidimensional cell death pathways.

Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death. The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC). In the "vicious cycle" of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC. Disrupting these cancer-stroma interactions would enhance treatment response. Methods: To disrupt this cycle…

Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts.

Progression of multiple myeloma (MM) is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles takes place. This cross-talk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease. In this paper, we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. We found that 5TGM1 sEVs, or 'exosomes', not only enhanced osteoclast activity, they also blo

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… Osteoclast differentiation, TRAP staining, and resorptive activity Osteoclast differentiation and resorptive activity were studied as previously described 13 , 14 . … We first analyzed whether GW4869 had any direct effects on 5TGM1 cells and osteoclasts in vitro. …

Establishment of a 3D-dynamic osteoblasts-osteoclasts co-culture model to simulate the jawbone microenvironment in vitro.

AIMS: We aimed to establish a 3D osteoblasts/osteoclasts co-culture system requiring limited amounts of human primary cells and useful as platform to 1. recapitulate an "oral bone microenvironment" in healthy or pathological condition, and 2. produce potential implantable cell constructs for regeneration of jawbone which can be negatively affected by bisphosphonates (BPs). MAIN METHODS: Osteoblasts from normal bone chips (hOBs) or from jawbone of patients taking BPs (hnOBs) were co-cultured with monocytes (hMCs) either in static (3D-C) or dynamic (3D-DyC) condition using the RCCS-4™ bioreacto…

Thrombospondin-1 regulates bone homeostasis through effects on bone matrix integrity and nitric oxide signaling in osteoclasts.

Thrombospondin-1 (TSP1), an endogenous antiangiogenic, is a widely expressed secreted ligand with roles in migration, adhesion, and proliferation and is a target for new therapeutics. While TSP1 is present in the bone matrix and several TSP1 receptors play roles in bone biology, the role of TSP1 in bone remodeling has not been fully elucidated. Bone turnover is characterized by coordinated activity of bone-forming osteoblasts (OB) and bone-resorbing osteoclasts (OC). TSP1-/- mice had increased bone mass and increased cortical bone size and thickness compared to wild type (WT). However, despite…

The Crosstalk between Osteoclasts and Osteoblasts Is Dependent upon the Composition and Structure of Biphasic Calcium Phosphates.

Biphasic calcium phosphates (BCPs), consisting of hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), exhibit good biocompatibility and osteoconductivity, maintaining a balance between resorption of the biomaterial and formation of new bone. We tested whether the chemical composition and/or the microstructure of BCPs affect osteoclasts (OCs) differentiation and/or their ability to crosstalk with osteoblasts (OBs). To this aim, OCs were cultured on BCPs with HA content of 5, 20 or 60% and their differentiation and activity were assessed. We found that OC differentiation is partially impaire…

Factors and mechanisms involved in the coupling from bone resorption to formation: how osteoclasts talk to osteoblasts.

Bone remodeling is the fundamental means by which the quality as well as quantity of the skeleton is maintained throughout adult life. When bone remodeling goes awry, a metabolic bone disease such as osteoporosis ensues. Among multiple phases of the complex remodeling process, we focus in this review on factors and mechanisms that are involved in the coupling of bone formation to preceding resorption.

Soluble decoy receptor 3 modulates the survival and formation of osteoclasts from multiple myeloma bone disease patients.

Decoy receptor 3 (DcR3), a member of the tumor necrosis factor (TNF) receptor superfamily, is known to be involved in cell survival and osteoclast (OC) formation. In this study, we show that malignant plasma cells and T lymphocytes from multiple myeloma (MM) bone disease patients, as well as Karpas 909, a human myeloma cell line, directly produce DcR3. By interacting with FasL, this molecule could inhibit OC apoptosis. In fact, the use of a neutralizing anti-DcR3 antibody induces a reduction of cell viability with a consequent increase of apoptotic cell number, the activation of caspase-8 and

LPS-stimulated human gingival fibroblasts inhibit the differentiation of monocytes into osteoclasts through the production of osteoprotegerin.

BACKGROUND: Understanding patterns of active and passive smoking among individuals with diabetes is essential for targeted prevention, improved glycemic control, and reduction of cardiometabolic complications. The Middle East and North Africa (MENA) region, which includes Iran, has the highest age-standardized diabetes prevalence worldwide, yet evidence on smoking patterns among Iranian adults with diabetes remains limited. METHODS: We used data from the 2021 WHO STEPS survey, a nationally representative population-based study conducted across all 31 provinces of Iran. Adults aged ≥ 25 years

Activation of P2Y but not P2X(4) nucleotide receptors causes elevation of [Ca2+]i in mammalian osteoclasts.

Extracellular nucleotides cause elevation of cytosolic free Ca2+ concentration ([Ca2+](i)) in osteoclasts, although the sources of Ca2+ are uncertain. Activation of P2Y receptors causes Ca2+ release from stores, whereas P2X receptors are ligand-gated channels that mediate Ca2+ influx in some cell types. To examine the sources of Ca2+, we studied osteoclasts from rat and rabbit using fura 2 fluorescence and patch clamp. Nucleotide-induced rise of ([Ca2+](i)) persisted on removal of extracellular Ca2+ (Ca), indicating involvement of stores. Inhibition of phospholipase C (PLC) with U-73122 or inh…

Stable association of PYK2 and p130(Cas) in osteoclasts and their co-localization in the sealing zone.

Bone resorption is initiated by osteoclast attachment to the mineralized matrix, cytoskeletal reorganization, cellular polarization, and the formation of the sealing zone. The present study examines the interaction between PYK2 and p130(Cas) (Crk-associated substrate), suggested to be part of the signaling pathway initiated by osteoclast adhesion. Using murine osteoclast-like cells (OCLs) and their mononuclear precursors (pOCs), generated in a co-culture of bone marrow and osteoblastic MB1.8 cells, we show that: 1) p130(Cas) is tyrosine-phosphorylated upon adhesion of pOCs to vitronectin or li

KLF2 interacts with AP-1 to negatively affect osteoclast differentiation and activity.

Osteoclasts function as the primary effectors of bone resorption and are essential for bone homeostasis. Krüppel-like factor 2 (KLF2) has been implicated in osteoclast differentiation, but its precise mechanism remains poorly understood. In this study, we aimed to investigate the role of KLF2 in osteoclast function by characterising osteoclastogenesis, maturation and activity and to explore the underlying biomechanism. We showed that KLF2 negatively regulates osteoclastogenesis by characterising the osteoclast number, size and protein markers; that it negatively regulates osteoclast maturation…

A NanoBiT-based high-throughput assay system for monitoring osteoclast fusion.

Osteoclast fusion is an essential step in the acquisition of bone-resorbing activity; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we developed a novel quantitative monitoring system for osteoclast fusion using NanoBiT, a split-luciferase technology. This system enabled sensitive detection of receptor activator of NF-κB ligand (RANKL)-dependent osteoclast fusion in RAW264 cells and bone marrow-derived macrophages, as well as interleukin-4 (IL-4)-induced foreign body giant cell fusion. The time-course analysis of luciferase activity du

Roxadustat Inhibits Osteoclast Differentiation and Function by Disrupting Cell Cycle Exit.

Bone remodeling relies on a balance between osteoclast-mediated resorption and osteoblast-mediated formation. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, promotes osteoblast differentiation but its effects on osteoclasts remain unclear. This study investigated roxadustat's impact on osteoclast differentiation and function in vitro using primary murine bone marrow-derived mononuclear cells differentiated with M-CSF and RANKL. Cell viability, TRAP staining, bone resorption assays, RNA-seq, flow cytometry, immunofluorescence, Western blot for p27, and rescue experiments w…

Circadian regulation of osteoclast lysosomal-resorption machinery: implications for osteoporosis therapy.

Osteoporosis (OP) is a systemic degenerative skeletal disorder characterized by reduced bone mass and compromised biomechanical properties, with its pathogenesis closely associated with excessive osteoclast activation and dysregulated bone resorption. Emerging evidence has revealed that the osteoclast lysosomal-resorption apparatus (LRA) serves not only as the principal effector system responsible for bone matrix degradation but also as a critical hub governing the circadian regulation of bone resorption. Disruption of circadian rhythms can impair LRA homeostasis and function, thereby promotin

PIDDosome deficiency impairs bone remodeling by increasing osteoclast ploidy and function.

Osteoporosis is a chronic disease driven by an imbalance between bone-building osteoblasts and bone-resorbing osteoclasts, whose hyperactivation can promote this condition. Osteoclasts are multinucleated cells, and their activity directly correlates with their ploidy level. Multinucleation associates with the accumulation of extra centrosomes that can activate the PIDDosome pathway. Depending on cell type, this can lead to a p53/p21-mediated cell cycle arrest, or BCL2-regulated apoptosis. Here, we report that the PIDDosome controls polyploidization in osteoclasts and its absence triggers bone …

Osteoclast-regulatory biomaterials: Direct cellular intervention and indirect microenvironment modulation.

Osteoclasts are central effector cells in osteolytic diseases. Their differentiation and resorptive activity are regulated by stage-dependent cellular programs and by spatially and temporally changing pathological cues. Aberrant osteoclast activation is therefore shaped by both cell-intrinsic signaling networks and extrinsic microenvironmental drivers. Recent advances in osteoclast-regulatory biomaterials include strategies that directly regulate osteoclast-lineage cells or modulate osteoclast-supportive microenvironments. In this review, we first summarize the biological basis of osteoclast o…

Prevotella copri impairs bone mass via osteoclast activation in mice.

Prevotella copri, a predominant commensal bacterium in the human gut, exhibits positive or negative correlations with multiple metabolic disorders through its abundance dynamics. Although its association with rheumatoid arthritis pathogenesis is established, the effect of P. copri on bone metabolism remains elusive. This study demonstrates that P. copri exposure induces systemic bone metabolic imbalance in both normal physiological murine models and in vitro-cultured bone marrow-derived adherent cells (BMDCs), which is characterized by exacerbated osteoclastogenesis. Notably, succinate acts as

A Tumor of Intrigue: Undifferentiated Carcinoma With Osteoclastic Giant Cells of the Urinary Bladder.

Undifferentiated carcinoma with osteoclastic giant cells (UCOGC) of the urinary bladder is a recently described entity classified as a subtype of poorly differentiated urothelial carcinoma, which is a form of invasive urothelial carcinoma. It is an extremely rare and aggressive malignancy that occurs predominantly in elderly men. The rarity of this neoplasm and its morphological similarity to other giant cell-rich lesions may present diagnostic challenges. Here, we present a case of urinary bladder carcinoma with a biphasic appearance. Histomorphological examination and immunohistochemical stu

Dihydrobaicalein suppresses osteoclast differentiation and mitochondrial transfer to prevent postmenopausal osteoporosis.

BACKGROUND: Postmenopausal osteoporosis (PMOP) is a prevalent metabolic bone disorder driven primarily by excessive osteoclast (OC) activation and enhanced bone resorption. The current therapeutic agents for PMOP remain limited by adverse effects associated with long-term use, underscoring the need for novel pharmacological alternatives with favorable safety profiles. Dihydrobaicalein (DIH), a polyhydroxylated flavanone compound, has demonstrated promising anti-inflammatory, antioxidant, and immunomodulatory activities,yet its therapeutic potential and mechanisms of action in PMOP treatment re