Disruption of the microenvironmental ecosystem in subchondral bone marrow lesions: Roles in osteoarthritis pathophysiology, pain and progression.

Introduction

Osteoarthritis (OA) is the most prevalent joint disorder [ 1 ], affecting over 500 million people globally, causing significant pain, loss of mobility and physical disability [ 2 ]. According to the World Health Organization (WHO) and the Global Burden of Disease (GBD) study [ 3 , 4 ], OA is one of the significant contributors to years lived with disability among all the musculoskeletal conditions 1 . Therefore, the WHO has designated 2021–30 the decade of healthy ageing, highlighting the need to address this serious disease, which strongly affects functional ability and quality of life. The main risk factors for OA include aging, obesity, joint injury, mechanical overload, genetic predisposition, and hormonal changes [ [5] , [6] , [7] ]. OA is more prevalent in older people (about 70% are older than 55), and one of the direct consequences of the rising incidence of OA is the burden placed upon healthcare systems globally, including the demand for joint replacements [ 8 ].

Early diagnosis is important for more effective long-term management of OA, but it remains highly challenging due the slow progression and asymptomatic nature of the disease in the very early stages [ 9 ]. Conventional imaging with X-ray radiography is widely used to confirm the clinical diagnosis of OA, but it fails to detect early structural changes in joint tissue compartments [ 10 ]. While MRI and advanced imaging modalities provide greater sensitivity, their high cost and limited accessibility hinder widespread clinical use [ 11 ]. MRI-based tools and analytic methods can be applied in clinical trials of investigational disease-modifying OA drugs (DMOADs) with a particular emphasis on knee OA [ 12 ].

OA treatment remains primarily symptomatic, focusing on pain management and functional improvement [ 13 ], as no disease-modifying therapies are currently available [ 14 ]. The heterogeneity of OA presents challenges in developing and testing new therapies, highlighting the need for precision medicine approaches integrating imaging biomarkers with molecular and clinical data [ 15 , 16 ]. Omics technologies and deep phenotyping approaches have the capacity to advance our understanding of the cellular and molecular taxonomy and the pathogenesis of the disease [ 17 , 18 ]. However, despite more than 30 years of research we do not yet have a clear molecular understanding of the disease in order to develop phenotype and endotype targeted therapies [ 19 , 20 ].

This narrative review article will summarize the content of two invited presentations at the International Workshop on Osteoarthritis Imaging (IWOAI) organized by the International Society of Osteoarthritis Imaging (ISOAI) 2 in Lausanne, Switzerland in June 2023 and in Marrakesh, Morocco in June 2024. The discussion will largely focus on the role of subchondral bone in OA pathophysiology and the emerging concept of mechanical and inflammatory disruption of the cellular bone marrow (BM) microenvironmental ecosystem [ 21 ] (also known as the BM niche) in BM lesions (BMLs) [ 22 , 23 ] and the cellular and molecular events that follow (see Fig. 1 ). The authors propose a new hypothesis implicating mechano-inflammatory disruption of the BM niche, unresolved inflammation, uncontrolled fibrosis as key pathophysiological drivers of pain and structural disease progression in OA, along with synovitis, joint effusion and osteophytes. Fig. 1 Tissue and cellular alterations in the bone marrow microenvironment in osteoarthritis (OA). This schematic illustrates some of the key events outlined in Table 1 , Table 2 , comparing a healthy bone marrow microenvironment (left) with a bone marrow lesion (BML) where the microenvironmental niche has been disrupted (right) in OA. In a healthy bone marrow microenvironment, there is balance between bone formation and resorption, regulated nerve signaling, balanced immune cell activity that supports resolution and repair. Furthermore, there is normal microvascular function, adipocyte function, and extracellular matrix (ECM) homeostasis. In the BML microenvironment, this balance is disrupted, resulting in structural and cellular dysfunction, affecting osteoblasts, osteoclasts, endothelial cells, immune cells, adipocytes, fibroblast-like cells, and nerves, leading to dysregulated inflammatory, catabolic, vascular, and fibrotic processes. Levels of pro-inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) are elevated, promoting macrophage activation and amplifying catabolic and inflammatory signalling. Neo-vascularization and neo-innervation are driven by several growth factors, including platelet-derived growth factor-BB (PDGF-BB), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), resulting in abnormal angiogenesis, nerve sprouting, and hypersensitization. Many of these processes are temporally regulated, including the initiation of receptor activator of nuclear factor kappa-Β ligand (RANKL) / osteoprotegerin (OPG) imbalance in subchondral bone and inflammation. This is followed by elevated VEGF, transforming growth factor beta (TGF-β), wingless-related integration site (Wnt)/β-catenin dysregulation, resulting in elevation of NGF, matrix metalloproteinases (MMPs), and aggrecanases such as ADAMTS-5. Furthermore, adipocyte hypertrophy and metabolic dysregulation driven by obesity, further disturb marrow homeostasis, by promoting macrophage recruitment, activation of fibroblast-like cells, and increasing TGF-β expression, resulting in ECM remodeling and fibrosis. Image created in BioRender https://BioRender.com . Fig 1 dummy alt text

Subchondral bone in OA

Subchondral bone, located immediately underneath articular cartilage, plays a key role in the pathophysiology of OA [ 24 ]. Anatomically, it comprises the subchondral bone plate and the underlying trabecular bone, forming a structural unit that provides structural, biomechanical and nutritional support to the overlying articular cartilage [ 25 ]. Subchondral bone absorbs and distributes mechanical loads during joint loading and provides the framework for bone-cartilage cross-talk [ 26 ]. In the early stages of OA, subchondral bone undergoes significant cellular and molecular alterations (see Fig. 1 , Table 1 , Table 2 ) before any noticeable radiographically detectable cartilage degradation occurs [ [27] , [28] , [29] ]. These early changes include increased bone mineral turnover, leading to a thinner and more porous subchondral bone plate, as well as remodeling of the trabecular bone architecture [ 30 , 31 ]. Over time, these structural modifications can result in BM lesions and the formation of osteophytes [ 32 , 33 ]. These structural changes not only compromise the mechanical integrity of the joint, but also contribute to pain and disease progression. Understanding the early alterations in the subchondral bone microenvironment is crucial for developing targeted interventions aimed at halting or reversing OA progression. Table 1 Summary of the key cellular events and main molecular changes in bone marrow (BM) lesions (BMLs) in subchondral bone in osteoarthritis (OA). The process begins with microdamage in subchondral bone extracellular matrix (ECM) [ 22 ] following mechanical (i.e. traumatic) and /or inflammatory events. The inflammatory response is initiated with the recruitment of activated macrophages that release pro-inflammatory cytokines (i.e. interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumour necrosis factor alpha (TNF-α)) are elevated, along with several other genes including interleukin 11 (IL-11) and versican (VCAN) [ 119 ], driving inflammation and ECM degradation [ 120 ]. Osteoclasts are then activated and resorb the calcified matrix, causing microfractures and changes in the subchondral bone microarchitecture. A number of mediators are released to inhibit bone ECM production, including increased production of sclerostin, which inhibits osteoblast activity, contributing to abnormal bone remodeling. Repair attempts are initiated by osteoblasts recruited to the lesion to repair the bone, although their efforts are often inadequate due to the ongoing osteoclastic activity, inflammation and altered catabolic signaling [ 121 , 122 ]. Mesenchymal stem cell (MSCs) are also attracted to the lesion site and differentiate into osteoblasts or chondrocytes, contributing to repair or further pathology. A number of mediators are released in response to inflammation and hypoxia to stimulate angiogenesis and nerve invasion. Vascular endothelial growth factor (VEGF) stimulates formation of new microvessels to supply the lesion with nutrients and immune cells, exacerbating the inflammation but also supporting repair processes, including those observed during fracture healing [ 123 , 124 ]. Nerve fibers grow into the lesion area, contributing to increased nociception. pain perception. The inflammatory and catabolic processes in the BML stimulate cartilage degradation and cellular changes, beginning with immunometabolic [ 117 , 118 ] and phenotypic [ 125 ] alterations in chondrocytes followed by chondrocyte apoptosis, further exacerbating joint dysfunction. The local release of prostaglandins (i.e. prostaglandin E 2 , PGE 2 ) promotes further pain responses through its effects on inflammation and osteoclastogenesis. The changes alter the cellular and molecular phenotype of cells in the subchondral bone, leading to cellular and molecular disruption of the microenvironmental ecosystem of the subchondral bone [ 68 ]. Matrix metalloproteinases (MMPs) are upregulated and activated, leading to further degradation and remodeling of the ECM, further disrupting the structural integrity of the bone-cartilage interface. Formation and accumulation of calcium-phosphate complexes contributes to ECM calcification and hypertrophy in chondrocytes [ 126 ]. There is little published information about alterations in the environmental niche of the adipose tissue in the BM. In this paper we hypothesize that the microenvironment of the BM drives changes the biology of adipose cells and inflammatory cells through upregulation and release of adipokines, contributing to inflammation and metabolic dysfunction. driving further disease progression. Table 1 dummy alt text Key Cellular Events (most likely temporal sequence) Main Molecular Changes (proposed temporal sequence) 1. Microdamage accumulation: Mechanical stress leads to the development of microcracks and microfractures in subchondral bone. 1. RANKL/OPG imbalance: Early upregulation of RANKL and downregulation of OPG initiate osteoclastogenesis. 2. Osteoclast activation: Increased osteoclast activity causes excessive bone resorption and trabecular thinning. 2. Pro-inflammatory cytokine release (IL-1β, TNF-α, IL-6): Early inflammatory response exacerbates bone loss. 3. Angiogenesis: Abnormal blood vessel formation occurs in response to hypoxia and inflammation. 3. VEGF upregulation: Promotes microvascular invasion and contributes to abnormal angiogenesis. 4. Inflammatory cell infiltration: Activated macrophages, T cells, and mast cells migrate into the subchondral bone marrow. 4. TGF-β overexpression: Drives fibrosis and ECM remodeling in the bone marrow. 5. Fibrosis: Fibrotic tissue replaces normal bone marrow ECM, altering the microenvironment and impairing cellular function. 5. Wnt/β-catenin pathway dysregulation: Disrupted signaling impairs osteoblast-mediated bone formation. 6. Adipocyte accumulation: Increased adipogenesis occurs in the bone marrow, contributing to metabolic changes. 6. Leptin and adiponectin dysregulation: Release of adipokines contribute to inflammation and metabolic dysfunction. 7. Nerve sprouting: Sensory nerves grow into the subchondral bone, contributing to pain. 7. NGF overexpression: Enhances nerve growth and sensitization, amplifying pain signaling. 8. Chondrocyte hypertrophy and cartilage degradation: Chondrocyte-like cells in subchondral bone contribute to cartilage breakdown. 8. MMP and ADAMTS upregulation: Degrade cartilage and exacerbate OA progression. Table 2 Key cell types, their primary functions in subchondral bone marrow lesions (BMLs) in osteoarthritis (OA), and the key molecules involved in the biological processes that occur in BMLs. TRAP ( Tartrate-resistant acid phosphatase ) and Cathepsin K are key enzymes involved in osteoclast-mediated bone resorption, regulated by RANK ( Receptor activator of nuclear factor-κB ), RANKL ( RANK ligand ), and NFATc1 ( nuclear factor of activated T-cells 1 ). Osteoblast activity is marked by ALP ( alkaline phosphatase ), RUNX2 ( Runt-related transcription factor 2 ), OCN ( osteocalcin ), COL1A1 ( collagen type I alpha 1 ), and SOST ( sclerostin ), a negative regulator of bone formation. MSCs express CD73, CD90, and CD105, with differentiation markers SOX9 ( SRY-box transcription factor 9 ), RUNX2, and COL2A1 ( collagen type II alpha 1 ). Osteocytes express sclerostin (SOST), fibroblast growth factor 23 (FGF23), connexin 43 (Cx43) and matrix extracellular phosphoglycoprotein (MEPE). SOST is the osteocyte-derived inhibitor of Wnt/β-catenin signaling, capable of suppressing bone formation. FGF23 regulates phosphate excretion and vitamin D metabolism in the kidney, linking bone metabolism to renal function. Cx43 is a gap junction protein mediating osteocyte communication and mechanotransduction. MEPE is an osteocyte-secreted protein modulating bone mineralization. Chondrocyte catabolic activity is driven by MMP13 ( matrix metalloproteinase-13 ), ADAMTS5 ( a disintegrin and metalloproteinase with thrombospondin motifs 5 ) and other proteases. Neo-vascularization is driven by vascular endothelial growth factor ( VEGF). Endothelial cells express CD31 ( platelet endothelial cell adhesion molecule ), VEGF (mainly produced and secreted in an autocrine fashion), ANGPT2 ( angiopoietin-2 ), and vWF ( von Willebrand factor ). Macrophages are distinguished by CD68, with M1 expressing CD80 and pro-inflammatory TNF-α ( tumour necrosis factor- α), while M2 express CD163, CD206, and anti-inflammatory IL-10 ( interleukin-10 ). Sensory nerve fibers and neurons involved in OA pain express CGRP ( calcitonin gene-related peptide ), NPY ( neuropeptide Y ), TRPV1 ( Transient receptor potential vanilloid 1 ). Sensory neurons express the nerve growth factor (NGF) receptor TrkA (and p75^NTR), making them highly responsive to NGF, which is produced by many other cells in the joint, particularly in response to abnormal mechanical loading and inflammation. Fibroblasts contribute to extracellular matrix (ECM) remodeling via α-SMA (α smooth muscle actin ), COL1A1, FAP ( fibroblast activation protein ), TGF-β ( Transforming growth factor-beta ), and MMPs ( matrix metalloproteinases ). Adipocytes from marrow fat secrete pro-inflammatory adipokines, including leptin, adiponectin, resistin, and express PPARγ ( peroxisome proliferator-activated receptor γ ), a key regulator of adipogenesis. Table 2 dummy alt text Cell Type Functions in BML Disruption Key Molecules Involved in the Biological Processes Involved in BMLs Osteoclasts Bone resorption, leading to subchondral bone remodeling and sclerosis TRAP, cathepsin K, RANK, RANKL, NFATc1 Osteoblasts Dysregulated bone formation, contributing to sclerosis and osteophytes ALP, RUNX2, OCN, COL1A1, Osteocytes Mechanobiological and molecular roles in the development and progression of BMLs. SOST (sclerostin), FGF23, Cx43, MEPE Mesenchymal stem cells (MSCs) Impaired differentiation, defective repair of bone and cartilage CD73, CD90, CD105, SOX9, RUNX2, COL2A1 Chondrocytes Hypertrophy, apoptosis, and catabolic activity leading to cartilage loss MMP13, ADAMTS5, VEGF Endothelial cells Pathological angiogenesis, increased permeability, and inflammation CD31, VEGF, ANGPT2, vWF Macrophages (M1/M2) M1: Pro-inflammatory response, M2: Anti-inflammatory & tissue repair CD68, CD80 (M1), CD163, CD206 (M2), TNF-α, IL-10 Sensory nerve fibers and neurons Neurogenic inflammation, pain sensitization in OA CGRP, NPY, TRPV1, NGF Fibroblasts ECM remodeling, fibrosis, and cytokine production α-SMA, COL1A1, FAP, TGF-β, MMPs Adipocytes (from marrow fat) Secrete pro-inflammatory adipokines that exacerbate OA pathology Leptin, adiponectin, resistin, PPARγ

Many preclinical animal models have been developed to study the changes in the anatomy of subchondral bone in spontaneous and experimentally induced models of OA [ 34 , 35 ] and evaluate the efficacy of novel therapeutic agents. Pre-clinical models have important limitations and do not necessarily represent the global changes that occur in human OA [ 36 ]. Therefore, it is crucial to test novel therapeutics in appropriate translational models [ 37 ].

Bone marrow lesions (BMLs)

From an imaging perspective, BMLs are key structural abnormalities in OA and we have known for some time that they are strongly associated with pain [ 38 , 39 ], interact with synovitis [ 40 ] and facilitate structural disease progression [ [41] , [42] , [43] ]. Published data from The Osteoarthritis Initiative (OAI) 3 [ 44 , 45 ] and other clinical studies have demonstrated that BMLs, detected primarily through magnetic resonance imaging (MRI), appear as areas of altered signal intensity within the subchondral bone, reflecting bone marrow oedema, fibrosis, and microdamage [ [46] , [47] , [48] , [49] ]. Advanced MRI techniques, such as T2-weighted fat-suppressed imaging and proton density sequences, have improved the sensitivity and specificity of BML detection, allowing for more precise characterization of their composition and extent [ 46 ]. The presence and size of bone marrow lesions BMLs correlate with OA structural severity and pain progression [ 50 , 51 ], with larger and expanding lesions being predictive of cartilage loss and worsening symptoms [ 52 ]. Data from the MOST study has shown that, the size of BMLs at baseline is associated with risk of subsequent cartilage loss and further structural deterioration. The absence of BMLs is generally associated with a reduced risk of progression [ 53 ].

BMLs serve as clinically significant and dynamic biomarkers of disease activity [ 54 ], fluctuating in response to biomechanical stress and therapeutic interventions [ 55 ]. Given their prognostic significance, BMLs are being explored as imaging biomarkers for OA [ 45 ], with potential applications in patient stratification for enhanced clinical trials and more effective treatment monitoring [ 56 ]. From the therapeutic monitoring perspective, longitudinal studies from the Foundation for the National Institutes of Health (FNIH) Osteoarthritis Biomarkers Consortium suggest that reductions in BML size are associated with symptomatic relief, highlighting their role as both biomarkers and potential therapeutic targets [ 57 ]. There is some evidence that reduction in BML size is associated with an increased risk of radiographic progression. However, these analyses may be subject to collider bias, as inherently only patients with existing BML have BML to lose. Careful analyses are needed to disentangle the associations between presence of BML, changes in BML, and progression risk [ 45 , 58 ]. Collider bias occurs when an exposure and outcome (or factors causing these) each influence a common third variable and that variable or collider is controlled for by design or analysis [ 59 ].

Along with imaging, biochemical markers can potentially become quite powerful adjunct tools for further molecular interrogation of BMLs. Studies conducted 20 years ago have suggested that BMLs observed on MRI are associated with Type II collagen degradation [ 60 ]. We know that biochemical markers of subchondral bone turnover are associated with BMLs and recent data from OAI has shown associations between markers of bone turnover and subchondral bone alterations [ 61 ] again with urinary C-terminal crosslinked telopeptide of type II collagen (CTX-II) being the marker that is most consistently associated with BMLs. However, it is important to note that this particular biochemical marker does not provide a robust correlation with incident pain and further investigation is required to identify a highly sensitive set of pain biomarkers that are associated with BMLs.

Developing tools and protocols that enhance our ability to monitor BMLs through non-invasive imaging techniques offers an opportunity to refine OA management by identifying high-risk patients and evaluating treatment efficacy. Future research should focus on integrating BML assessment into clinical practice and exploring targeted therapies that mitigate their impact on joint health.

Osteophytes

Osteophytes are bony outgrowths at joint margins, a well-recognized radiographic feature of OA [ 62 , 63 ] playing complex roles in disease progression and symptomatology [ 64 ]. Their development follows the “chondrophyte hypothesis”, which proposes that osteophytes originate from cartilaginous outgrowths at the osteochondral junction, that eventually become calcified and thus visible on X-ray radiography. Their development is driven by the process endochondral ossification and is accompanied with neurovascular invasion [ 65 ], bringing nerves and vasculature to anatomical regions that were previously devoid of such structures. Biomechanical stress, pro-inflammatory cytokines (e.g., IL-1 β), plus growth factors belonging to the family of growth differentiation factors (GDFs) (e.g., TGF-β, BMPs) [ 66 , 67 ], and altered joint biomechanics stimulate mesenchymal progenitor cells in the periosteum to undergo chondrogenesis, followed by progressive mineralization and bone formation [ 68 ], a process that appears to be a form of developmental recapitulation [ 69 ].

Imaging modalities such as X-ray radiography, computed tomography (CT), and MRI enable the detection and monitoring of osteophytes at various disease stages. While radiographs remain the standard for clinical assessment of osteophyte development in OA, MRI provides superior sensitivity in detecting early osteophyte formation and associated BM changes [ 70 , 71 ]. The presence, number and size of osteophytes are commonly used as radiographic markers of OA severity, yet their clinical implications remain nuanced. While osteophytes have been proposed to stabilize the joint by redistributing mechanical loads, they may also contribute to pain, stiffness, and reduced mobility, particularly when encroaching on adjacent soft tissues [ 64 ]. Short term changes in osteophytes are associated with longer term structural and symptomatic progression [ 72 ], highlighting the potential as a prognostic or efficacy of intervention biomarker. Their role as imaging biomarkers of OA progression is also supported by studies of biochemical markers such as urinary α-C-telopeptide of type I collagen (α-CTX), the first serological marker found to be associated with osteophyte burden [ 73 ].

There is a proposed established framework for histological classification of osteophytes according to the type of matrix they produce and the degree of classification within them [ 74 ]. Once again the use of pathophysiologically and clinically relevant preclinical and translational animal models can provide valuable comparative insights into osteophyte development and determine the true weight of their significance in joint disease [ 36 , 75 , 76 ].

In summary, more research is needed to understand the predictive value of uncalcified chondrophytes and calcified osteophytes in structural deterioration and treatment response in OA clinical trials. Understanding the “chondrophyte to osteophyte” transition may offer new therapeutic avenues for modifying OA progression.

Linking subchondral cysts to BMLs

A large body of published preclinical studies have demonstrated that subchondral cysts are fluid-filled cavities within the subchondral bone, commonly observed in experimental animal models of OA [ 29 , 34 , 77 ]. Their formation is explained by several theories, each supported by molecular and imaging evidence and linked to bone marrow lesions (BMLs) seen clinically in humans [ 78 ]. The synovial ingress theory proposes that cartilage defects allow synovial fluid to intrude into the subchondral bone, leading to cyst formation [ 79 ]. Indeed, MRI studies have visualized these fluid-filled cavities, partially supporting this mechanism. The biomechanical injury theory suggests that repetitive mechanical stress causes microfractures in the subchondral bone, resulting in cysts [ 79 ]. Again, MRI has detected BMLs, indicating areas of bone marrow oedema and microdamage, which may indeed precede cyst development. The vascular aging theory is an interesting hypothesis that proposes that age-related vascular changes impair blood flow to the subchondral bone, leading to necrosis and cyst formation. Advanced imaging techniques have identified reduced perfusion in subchondral regions, supporting this hypothesis. It is important to note that these theories are all sound and are supported by data. Furthermore, they are not necessarily mutually exclusive, and the proposed mechanisms may work together in a tightly regulated spatio-temporal fashion. Emerging imaging markers, such as dynamic contrast-enhanced MRI [ 80 ], are enhancing the study of vascularity and innervation in OA, as they have done in rheumatoid arthritis (RA) [ [81] , [82] , [83] ], providing deeper insights into the pathophysiology of subchondral cysts and their association with BMLs.

Subchondral bone, BMLs and pain pathways

OA pain is increasingly recognized as a complex, multifactorial process involving subchondral bone. Osteoclasts in subchondral bone play a key role in this process by producing mediators that induce sensory innervation. Therefore, the BM microenvironmental niche can be a potent driver of OA pain [ 23 , 84 ]. Inflammatory mediators such as prostaglandins, pro-inflammatory cytokines (i.e., interleukin 1 beta (IL-1β), tumour necrosis alpha (TNF-α)) [ 85 ], and nerve growth factor (NGF) [ 86 ] contribute to peripheral sensitization by activating nociceptive pathways within subchondral bone in OA [ 87 ], activating a plethora of channels and receptors involved in pain in peripheral nerves [ 88 , 89 ]. Recent preclinical studies have demonstrated that elevated secretion of platelet-derived growth factor-BB (PDGF-BB) by mononuclear preosteoclasts induces subchondral bone angiogenesis, contributing to OA development, providing yet another pathway that links articular cartilage and subchondral bone [ 90 , 91 ].

But how does it work? We make the assumption that BMLs and osteophytes, commonly detected by MRI, are associated with increased sensory nerve infiltration and the release of pain-promoting mediators [ 71 , 92 ]. Peripheral sensitization lowers the activation threshold of joint nociceptors, while central amplification in the spinal cord and brain further intensifies pain perception [ 93 ]. Additionally, neuronal sprouting and aberrant innervation within subchondral bone enhance pain signaling, resembling neuropathic pain mechanisms [ 84 ]

Emerging imaging modalities including PET and high-resolution MRI can visualize changes in bone innervation and vascularity, improving our understanding of how BMLs, osteophytes and the disturbed BM niche contribute to OA pain pathophysiology.

Biomechanical disruption of the BM microenvironment

The novel hypothesis proposed by the authors focuses on the mechanical and inflammatory disruption of BM microenvironment, or niche, within BMLs. In this context, abnormally high mechanical stress, effusion, oedema and persistent inflammation alter the BM niche, resulting in altered immunometabolism and disrupted cellular homeostasis in the BM microenvironment, potentially leading to vicious cycle of unresolved inflammation and extracellular matrix (ECM) fibrosis exacerbated by cellular stress, apoptosis, senescence and embryonic and developmental programs [ 94 , 95 ].

Testing this novel hypothesis would require a coordinated approach employing pre-clinical and translational animal models of OA and relevant data from a sufficiently large OA cohorts with extensive BML data, including imaging and biochemical markers. Although this represents a novel proposition in the field of OA, there is precedent for it in oncology and immunology. The proposed hypothesis actually mirrors existing observations in bone malignancies, where tumour-induced mechanical forces and inflammatory cytokines disrupt the BM niche (see Fig. 1 ), exacerbating the major hallmarks of cancer [ 96 , 97 ] and thus promoting highly disruptive cellular and molecular processes that sustain the tumour and support neoplastic growth [ 98 , 99 ]. Inflammation is a common feature of several hematological malignancies that reside in the BM and remodeling of the microenvironmental niches can facilitate immune evasion, activation of survival pathways favoring malignant hematopoietic cell maintenance, defense against excessive reactive oxygen species and protection from chemotherapy [ 100 ]. Malignancy-associated bone marrow inflammation appears similar across diseases at the systemic and organ levels, but it is driven by different effector cells and associated with distinct tissue remodeling at the level of cellular niches in acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma [ 101 ]. Similarly, in hematopoietic immunological disorders, persistent inflammation perturbs the BM niche, impairing the process of hematopoiesis, shifting the immune profile of cells in the BM niche and promoting fibrotic changes [ 102 ].

We now know that in OA such mechano-inflammatory disruption occur in a sustained manner [ 103 ] and factors that promote this process within BMLs may also drive pain and structural disease progression [ 104 ]. Therefore, in the context of clinical phenotypes and molecular endotypes of OA [ 19 , 105 ], unresolved inflammation within the BM niche can lead to the recruitment of multiple immune cells, including B-cells, T-cells, monocytes and macrophages that continue releasing pro-inflammatory mediators [ 106 ], sensitizing nociceptors and contributing to pain. Concurrently, uncontrolled ECM degradation and fibrosis can alter the microstructure and mechanical resilience of subchondral bone, exacerbating abnormal mechanical stresses on the overlying cartilage and accelerating joint degeneration [ 107 ], through activation of TGF-β signaling [ 108 ] and other dysregulated growth factor pathways. These important parallels between OA, hematopoietic malignancies and immune disorders suggest that targeting the mechano-inflammatory disruption of the BM niche and addressing fibrosis with anti-fibrotic drugs [ 109 ] can be viable therapeutic strategies in OA. From a cellular and molecular perspective, one of the key research priorities should be closer examination of the inflammatory, catabolic and angiogenic milieu within BMLs and how disruption of the BM niche contributes to nociceptive signaling, explaining their strong association with OA pain [ 38 , 39 , 44 ]

Further support for this hypothesis comes from research in the field of obesity. It is well established that obesity is one of the major risk factors for the development of OA [ 110 ] and there is a strong correlation between overweight, obesity, high body mass index (BMI) and OA pain [ 111 ]. There is emerging evidence that obesity drives disruption of the bone marrow BM physiological niche and can result in hematopoietic dysfunction [ 112 ]. Therefore, it would be worthwhile and interesting to examine the possibility that the weight loss drugs currently under investigation for the treatment of obesity such as glucagon-like peptide-1 receptor (GLP-1R) agonists could potentially also have beneficial impacts on the BM microenvironmental niche in subchondral bone of obese individuals with OA in addition to their known effects on bone metabolism [ [113] , [114] , [115] ] and the recently reported pain and function benefits in persons with obesity and knee OA [ 116 ].

Conclusions

We propose that mechano-inflammatory disruption of the BM microenvironmental ecosystem can occur in BMLs in OA. This scenario may be significantly exacerbated in obesity. Persistent inflammation and fibrosis in the BM niche may exacerbate joint pain and structural disease progression. Therefore, targeting these processes within the BM niche may hold significant promise for effective disease modification, while metabolic interventions [ 117 , 118 ] that directly target the BM could further mitigate OA progression. Weight loss and physical activity or a combination of weight loss drugs and physical activity can provide such immunometabolic interventions, taking us closer to our strategic target of disease modification and joint preservation. Advancing the science of OA imaging and specifically the functional imaging of BMLs will require development and testing of novel molecular probes for the cells that are involved in dynamic processes in BMLs.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Acknowledgments

This research is supported through the following funding mechanisms: Research Council of Finland through the 351568 and Profi6 336449 grants awarded to Ali Mobasheri at the University of Oulu. The European Structural and Social Funds through the Research Council of Lithuania (Lietuvos Mokslo Taryba), according to the Program Attracting Foreign Researchers for Research Implementation (Grant No. 01.2.2-LMT-K-718-02-0022 ); Horizon Europe (PROTO - Advanced PeRsOnalized Therapies for Osteoarthritis – TACKLING INFLAMMATION TO IMPROVE PATIENT OUTCOMES, Grant agreement ID: 101095635, https://cordis.europa.eu/project/id/101095635 and ENgineered CArtilage from Nose for the Treatment of Osteoarthritis (ENCANTO ) , Grant agreement ID: 101137315 , https://cordis.europa.eu/project/id/101137315 ). Ali Mobasheri also wishes to acknowledge networking support from the European Cooperation in Science and Technology (COST) Association, Action CA21110 – Building an open European Network on OsteoArthritis research (NetwOArk; https://cost.eu/actions/CA21110 ).

Editor Disclosure: The peer review process did not involve Editorial Board Member Jamie E. Collins, and the editorial decision-making was led by editors not involved in the creation of this manuscript.

https://www.who.int/news-room/fact-sheets/detail/osteoarthritis

https://www.isoai.org/

https://nda.nih.gov/oai