Subchondral bone contribution to osteochondral health and injury

Introduction

Research on osteochondral repair has traditionally focused on restoring articular cartilage, with less attention given to the underlying subchondral bone. However, recent studies have emphasized the critical role of subchondral bone health in determining the long-term success of cartilage repair procedures (1-3). The subchondral bone provides structural support to the overlying cartilage and influences the mechanical and biological properties of the joint. Consequently, alterations in the subchondral bone, such as changes in density, microarchitecture, and the formation of subchondral cysts (SCCs), can undermine the mechanical integrity of the osteochondral unit, leading to joint instability, pain, and repair failure (1,3-5).

Recent advances in imaging have further highlighted the importance of the subchondral bone. These techniques have revealed the presence of nano-pores in the subchondral plate, which facilitate solute transport and biochemical signaling at the osteochondral interface, suggesting their potential role in maintaining joint homeostasis. However, the mechanisms underlying these processes remain poorly understood (2,6,7).

Understanding the interplay between subchondral bone and cartilage is essential for both cartilage repair and osteoarthritis (OA). Features such as the histologic tidemark marking the transition to calcified cartilage, as well as subchondral bone remodeling and vascularization, are crucial for cartilage nourishment, metabolism, and repair outcomes, as are also increasingly recognized as key contributors to disease progression in OA (8-10). This review explores the contributions of subchondral bone to cartilage repair procedures and OA pain. By synthesizing recent translational and clinical research, it aims to elucidate the mechanisms driving subchondral bone alterations and their implications for developing targeted therapies that optimize clinical outcomes.

Anatomy, composition, and biomechanical role of subchondral bone

The subchondral bone is a specialized structural and functional component of the osteochondral unit, located directly beneath the articular cartilage. It consists primarily of trabecular bone interspersed with fatty bone marrow, and is capped by the cortical end plate (or articular bone plate), a porous structure that permits vascular penetration and communication with the overlying cartilage (9). Richly vascularized, the subchondral region contains arterial terminal branches that form sinusoids and drain into a venous plexus (9). This network supports the metabolic demands of cartilage, supplying over 50% of its required glucose, oxygen, and water, while also facilitating the removal of waste products (11). With aging, this vascular perfusion diminishes until the age of 70 years, potentially compromising cartilage nourishment and joint health (12).

Besides its fundamental role in cartilage nutrition, the subchondral bone functions as a shock absorber being even more effective than cartilage at dissipating mechanical forces (9). At the osteochondral junction, the undulating architecture of the tidemark and the gradual transition in stiffness—from soft cartilage to the stiffer calcified cartilage and finally to subchondral bone—play a key role in redirecting oblique shear forces into compressive and tensile stresses. This mechanical transformation reduces localized damage and allows the forces to be more safely transmitted to the underlying bone. It thereby absorbs approximately 30% of the mechanical loads during joint movement, effectively reducing stress concentration on the overlying cartilage. Residual forces that exceed this capacity are further distributed through the cortical bone and joint capsule, contributing to the overall mechanical resilience of the joint (13,14). Moreover, during physiological articular loading and unloading, both the cartilage and the subchondral region undergo coordinated deformation, allowing the osteochondral unit to effectively accommodate dynamic mechanical stresses. This deformation acts as a mechanotransductive stimulus, promoting cellular activities associated with the synthesis of proteoglycans and collagen within the osteochondral unit (9). Such mechanoresponsive behavior highlights the subchondral bone’s dual function—not only as a biomechanical buffer modulating load transmission, but also as a metabolically active interface that supports the structural and functional integrity of the overlying articular cartilage, thereby contributing critically to joint homeostasis.

Calcified cartilage layer (CCL)

The CCL is a specialized mineralized zone situated between the articular cartilage and the subchondral bone, anatomically defined by the upper tidemark and the lower cement line (15). It is composed of hypertrophic chondrocytes embedded within a calcified extracellular matrix consisting of type I collagen, sodium hyaluronate, and nanohydroxyapatite, forming a structurally and compositionally distinct interface (16). Functionally, the CCL serves as a mechanical and biochemical bridge within the osteochondral unit. By offering a gradient in stiffness—being significantly stiffer than uncalcified cartilage yet more compliant than subchondral bone—it minimizes shear stress during joint loading and enables efficient transmission of mechanical forces across the joint surface (17).

In addition to its biomechanical role, the CCL contributes to biochemical compartmentalization and communication. Its relatively low permeability regulates the diffusion of small solutes and signaling molecules while restricting vascular invasion from the subchondral bone, thereby preserving the avascular environment critical for articular cartilage function. This controlled exchange supports metabolic homeostasis and facilitates bone–cartilage crosstalk, essential for both joint development and maintenance. The integrity of the CCL is tightly linked to subchondral bone health, and together they function as a cohesive unit. Disruption in one component—such as in OA—can propagate structural and biochemical changes in the other, emphasizing their interdependence in both physiological and pathological states (18).

Bone remodeling

Bone remodeling is the constant balance between bony formation and resorption in concerted effort to maintain bony substructures, a continuous mechanism involving the coordinated effort of osteoclasts and osteoblasts. Bone remodeling occurs at specialized regions known as Bone Metabolism Units, which are essential for maintaining the skeleton’s structural integrity and adapting to mechanical loads. A tightly regulated balance between osteoclast and osteoblast activity ensures bone homeostasis, where bone resorption and formation occur simultaneously. This process is also important for injury repair and recovery, as it enables the bone to respond to damage and mechanical stress. Disruptions in this balance, such as those seen in diseases like osteoporosis or OA, can lead to weakened bone structure, impaired healing, or subchondral bony sclerosis with or without associated subchondral plate or trabecular fractures, underlining the importance of efficient remodeling for maintenance of skeletal health (19).

After injury, subchondral plate regeneration is a dynamic process governed by mechanical loading, which enhances remodeling through increased vascularity and cellular activity. Mechanical stress stimulates vascular invasion into the calcified zone, delivering osteogenic and remodeling cells critical for endochondral ossification, the process by which calcified cartilage is converted to bone (20,21). Areas of greater mechanical loading, such as the more stressed regions of the femoral head, exhibit 25% more vascularity and elevated remodeling activity compared to less loaded areas (21). Remodeling activity declines with age, particularly until the sixth or seventh decade, but a resurgence in both vascularity and remodeling is observed in older age, reaching levels comparable to those in younger individuals (21). Despite age-related thinning of the calcified zone, the interplay between mechanical forces and biological responses ensures the subchondral plate adapts to stress, reinforcing joint integrity and facilitating repair (20). These findings highlight the importance of mechanical loading as a key driver of subchondral plate regeneration, underscore its therapeutic potential in promoting joint health and recovery, and stress the importance of active rehabilitation after osteochondral repair.

Microarchitecture

The trabecular bone, with its network of interconnected struts and plates, not only serves to distribute mechanical forces but also provides a large surface area for cellular activity involved in bone remodeling and harboring hematopoietic elements. The microarchitecture, including trabecular thickness, density, and connectivity, determines bone’s ability to withstand stress and contributes to overall skeletal strength. Changes in this microarchitecture, such as those seen in aging, disease, or after mechanical loading, can significantly affect bone’s structural integrity. For example, in conditions like osteoporosis or OA, microarchitectural alterations such as thinning of trabecular bone and loss of connectivity can lead to increased fragility and risk of fractures. The proportional contribution of cellular dysfunction to this degeneration, which appears to be accelerated following insults such as chemotherapy or irradiation, and the degree of underlying stem cell failure in such instances are currently unknown. These changes highlight the importance of maintaining bone health at both the cellular and structural levels to preserve the skeleton’s capacity to withstand functional stresses (19).

Disruption of trabecular microarchitecture in subchondral bone has implications for joint integrity and long-term skeletal function, particularly when improper repair strategies are employed. Corticalization of the subchondral bone, rather than restoration of trabecular architecture, may exacerbate joint degeneration by increasing subchondral stiffness, impairing biomechanical load distribution, and reducing the bone’s ability to absorb shock. Experimental models, such as prolonged mechanical loading in sheep, have demonstrated that hard surface exposure results in increased cortical thickness of the subchondral plate and altered trabecular patterns, leading to joint stiffening and imbalanced tibiofemoral load transfer (22). Clinically, subchondral cementation following curettage of periarticular giant cell tumors, while effective for immediate pain relief, has been associated with progressive joint degeneration, including cartilage lesions and synovitis, further illustrating the role of native subchondral microarchitecture in dissipating mechanical forces (23). These outcomes underscore the critical importance of preserving or restoring trabecular integrity to optimize subchondral remodeling, shock absorption, and joint biomechanics following injury or surgical intervention.

Innervation of bone

While cartilage is aneural, in healthy bone, sensory innervation plays a crucial role in maintaining homeostasis and responding to mechanical and chemical changes. The subchondral bone is richly innervated by sensory nerve endings, primarily nociceptors, responsible for detecting noxious stimuli. These sensory fibers, which include both myelinated Ad fibers that transmit sharp, fast pain, and unmyelinated C fibers that convey slow, aching pain, are distributed along various pathways, such as nutrient foramina and Haversian canals, and branch into the periosteum, bone marrow, and subchondral bone (24). These nerve fibers are involved in mechanotransduction, which allows bones to adapt to load and stress, and support bone remodeling and homeostasis, without inducing pain under normal conditions (6,25). Furthermore, sympathetic nerves within the subchondral bone marrow are assumed to play a role in regulating bone metabolism and contributing to pain mechanisms associated with joint diseases (26,27).

Subchondral bone in acute cartilage lesions

Injury to cartilage and the underlying subchondral bone initiates a complex cascade of events crucial for repair and regeneration. One key response is the proliferation of sensory and sympathetic nerve endings, which orchestrate the delivery of essential growth factors to facilitate healing. Acute cartilage injuries disrupt the architecture and function of the subchondral bone (Figure 1), triggering immediate changes that are vital for maintaining the integrity of the osteochondral unit. This disruption sets off a physiological process characterized by early bone resorption, followed by a remodeling phase resembling fracture healing, which can last from 3 to 12 months depending on the circumstances (3).

Figure 1 An 18-year-old male basketball player with a pivoting injury to his knee suffering a full thickness chondral lesion. Subsequently continued to play basketball for 2 months, with persistent knee pain and effusions. Arrows indicate the cartilage defect at the lateral femoral condyle with surrounding bone marrow lesions.

There is a close relationship between nerves and growth factors which is well-illustrated in mandibular fracture models, where exogenous nerve growth factor (NGF) accelerates nerve reflex restoration while significantly increasing bone morphogenetic proteins (BMP)-9 and vascular endothelial growth factor expression. These factors collectively promote enhanced osteogenesis and angiogenesis. Histological analyses of NGF-treated fractures reveal robust callus formation and vascularization compared to controls, underscoring the critical interplay between neural signals and growth factors in bone repair (28).

In the deeper regions of cartilage defects, mesenchymal cells can differentiate into osteocytes, forming immature bone. This repair tissue initially aims to restore the original level of the subchondral bone; however, over time, it may advance toward the joint space, contributing to pathological changes. These changes include the upward migration of the subchondral bone plate, formation of intralesional osteophytes, and development of subchondral bone cysts. Such alterations not only affect the mechanical integrity of the subchondral bone but also have significant implications for cartilage repair outcomes. For instance, upward migration of the subchondral bone plate can reduce the thickness of the overlying articular cartilage, resulting in uneven load distribution and accelerating cartilage degeneration (3).

In urodele amphibians (e.g., axolotls), known for their exceptional regenerative capacity, fibroblast growth factor and BMPs synthesized in neural cells are transported to regenerating tissues via axonal pathways. These factors directly influence regeneration, with knockdown experiments confirming their essential role in successful limb regeneration (29). These findings highlight the fundamental role of nerve signals as early responders to injury, mediating both structural and biochemical responses to promote repair. This may reflect an evolutionarily conserved mechanism, whereby the pain response is closely linked to activation or repair pathways. While this neural contribution is undoubtedly critical, the exact mechanisms remain incompletely understood, marking an exciting frontier for further research.

Preserving the subchondral plate in osteochondral surgery

Optimizing cartilage repair requires a comprehensive approach that considers the structural and biological integrity of the entire osteochondral unit. Traditional cartilage repair techniques—particularly bone marrow stimulation (BMS) methods such as microfracture, subchondral drilling, and abrasion arthroplasty—remain widely used due to their simplicity and accessibility (3). However, accumulating clinical and preclinical evidence highlights that these procedures can induce adverse changes in the subchondral bone, including upward migration of the bone plate, formation of intralesional osteophytes, development of SCCs, and disruption of the osseous microarchitecture (1-3). These changes impair joint biomechanics, reduce cartilage thickness, and accelerate tissue degeneration, ultimately compromising the stability and quality of the repair (2,3). Consequently, the use of BMS techniques has become a topic of intense discussion, especially regarding their long-term effects on subchondral bone health and overall repair outcomes.

Clinical studies further demonstrate that these subchondral alterations negatively affect patient outcomes. Subchondral bone overgrowth and cystic degeneration are frequently observed following both microfracture and autologous chondrocyte implantation (ACI), and are associated with increased pain, reduced joint function, and a higher risk of repair failure. Notably, when the subchondral bone remains structurally intact, outcomes following microfracture are significantly more favorable (6). Preserving the integrity of the subchondral plate is therefore critical for long-term success. Recent findings even suggest that the presence of viable cells in the cartilage layer may not be essential for effective repair. Instead, it may be the catabolic activity of living chondrocytes—rather than their mere presence—that contributes to cartilage degeneration following injury (5). These insights emphasize the need for further research to clarify the relative contributions of cartilage and subchondral bone in osteochondral repair. However, current evidence strongly indicates that subchondral bone plays a more pivotal role than previously recognized and should receive greater attention in both surgical strategy and regenerative approaches.

Optimizing subchondral bone treatment in cartilage repair: shifting the focus beyond chondral restoration

Refinement of surgical technique is essential to protect the subchondral bone and improve long-term outcomes in osteochondral repair. BMS procedures require meticulous defect preparation, including complete removal of the CCL while strictly avoiding damage to the subchondral plate. Curettes are preferred over motorized instruments due to their superior control and preservation of subchondral integrity. Vertical, stable defect margins should be created without undermining adjacent cartilage. To ensure reliable marrow access—particularly in sclerotic bone—perforation depths of 3–4 mm are generally recommended to reach the trabecular zone and access mesenchymal stem cells (MSCs). Shallow microfractures may fail to penetrate this zone adequately, especially in compromised subchondral architecture (30).

In recent years, there has been renewed scientific interest in using thin (≤1 mm), deeper drill perforations rather than traditional awl-based microfracture techniques. Preclinical studies have demonstrated that this approach results in less disruption of the subchondral bone and leads to improved quality of the cartilage repair tissue (31-33). Instrument parameters such as diameter and density also influence the mechanical stability of the subchondral plate. Smaller-diameter awls (~1.0 mm), closely matching the native trabecular spacing, reduce bone compaction and are associated with improved remodeling and fewer cystic complications (34). In contrast, larger or overly dense perforations may enhance MSC access but at the cost of mechanical weakening and an increased risk of adverse remodeling. Optimizing these variables is essential for achieving the desired biological effect without compromising subchondral structure.

These considerations extend to cell-based approaches such as ACI, which, despite bypassing direct subchondral penetration, has also been linked to osseous changes. Upward migration of the subchondral plate has been observed in up to one-third of ACI-treated lesions at long-term follow-up, particularly in larger defects or those located at the lateral femoral condyle (35,36). Such alterations can compromise repair durability and function, underscoring the importance of evaluating subchondral bone health when selecting and planning treatment strategies.

Strategies to preserve and enhance subchondral bone structure during osteochondral repair include the use of osteochondral allografts with optimized thickness (5–8 mm), which ensures mechanical compatibility and reduces immunogenic responses. High-pressure lavage with saline or CO₂ can further improve graft integration by removing marrow elements that may contribute to immune rejection or delayed incorporation. Adjunctive therapies, such as the injection of marrow aspirate into the prepared defect or backside venting, may also support improved biological integration between the graft and host bone. Although promising, these approaches require further standardization and validation through robust clinical studies (37).

Recently, matrix-induced autologous chondrocyte implantation (MACI) has increasingly been combined with autologous spongiosa grafting for the treatment of osteochondral lesions. This technique is particularly used for defects larger than 3–4 cm², where autologous osteochondral transplantation reaches its limitations. In these cases, the damaged bone is first removed and the defect is subsequently filled with autologous cancellous bone, typically harvested from the iliac crest or tibial head. MACI is then performed according to established protocols. In deeper defects, an alternative approach involves the transplantation of a monocortical bone block, also harvested from the iliac crest. This method offers the potential advantage that the cortical layer of the graft resembles the native subchondral bone, possibly enhancing structural integration and biomechanical stability (38).

Rehabilitation protocols following cartilage repair have traditionally delayed weight bearing due to uncertainty regarding the mechanical integrity and load-bearing capacity of the repair tissue. However, it remains unclear whether different postoperative loading regimens can help mitigate subchondral complications such as upward migration of the bone plate or the formation of intralesional osteophytes, particularly given the increased biomechanical stress placed on the subchondral bone beneath cartilage defects (39). At the same time, controlled weight bearing and joint movement are essential for maintaining joint homeostasis, as mechanical loading plays a critical role in modulating chondrocyte differentiation and stimulating articular matrix synthesis within the graft. Notably, clinical evidence has shown that accelerated weight-bearing protocols combined with intensive rehabilitation following second-generation ACI can result in favorable outcomes without compromising graft integrity (40). In addition to surgical and rehabilitative measures, evolving biological strategies aim to further support subchondral bone preservation and integration (41).

Ultimately, successful cartilage repair depends not only on resurfacing the defect, but on restoring a functionally integrated osteochondral unit. This requires a shift away from cartilage-centric approaches toward strategies that holistically address both cartilage and subchondral bone—emphasizing surgical precision, biologically informed interventions, individualized postoperative care, and long-term structural preservation to ensure durable clinical outcomes.

Subchondral bone in OA: a complex interplay of pathological changes

In OA, pathological changes in the subchondral bone—such as microdamage, bone marrow lesions (BMLs), and the formation of SCCs—contribute to joint degeneration and pain (19,24,26,27). BMLs, which are areas of bone marrow edema and inflammation, are characterized by high metabolic activity, angiogenesis, and bone turnover. They are associated with structural changes and osteochondral damage. Although commonly linked to OA, BMLs are not exclusive to it and can arise from other conditions, such as cartilage injuries (42).

SCCs often develop in response to mechanical stress and maladaptive bone remodeling, either within an OA environment or after cartilage repair procedures. These cysts compromise subchondral bone integrity, disrupt load distribution, and worsen joint degeneration, thereby correlating with more severe disease. Their presence underscores the need for targeted prevention and management strategies during osteochondral repair to ensure better outcomes (3,6,43,44).

In addition to neural changes, blood vessels play a key role in subchondral bone changes in OA. Increased vascularization is a hallmark of OA, particularly in regions undergoing pathological remodeling. Studies have revealed that OA patients’ femoral heads exhibit a significantly higher density of nerve fibers than those with fractures. These fibers are closely associated with blood vessels, underscoring the strong relationship between vascularization and nerve growth in OA (27).

As OA progresses, neurovascular remodeling becomes increasingly pronounced, with nerve fibers extending from the subchondral bone into the cartilage in response to degeneration and remodeling processes. These nerves are often morphologically abnormal and rich in inflammatory neuropeptides, further sensitizing nociceptors and establishing a vicious cycle of persistence in pain (45,46). Histological evidence confirms increased nerve density and altered nerve function at these junctions, which likely contributes to the heightened pain sensitivity observed in OA patients. The interplay between vascularization and neurovascular invasion further complicates OA-related pain, as NGF drives both vascular and nerve proliferation, sensitizing pain pathways and intensifying nociceptive signaling (19,24,26,27,45).

In addition to sensory nerves, sympathetic nerve fibers are also present at the osteochondral junction. Sensory fibers express markers such as calcitonin gene-related peptide and substance P, both of which are crucial in mediating pain perception (26). These sensory and sympathetic fibers also interact to regulate blood flow and mediate responses to injury, further amplifying the pain experience in OA (26).

Taken together, neurovascular invasion represents an important contributor to pain exacerbation and the acceleration of joint deterioration in OA. Effective management strategies must address these neural and vascular pathways alongside structural damage to improve therapeutic outcomes.

Structural changes in OA: BMLs and SCCs

Structural changes within the subchondral bone, including the development of BMLs and SCCs, are recognized hallmarks of OA. These alterations are strongly associated with pain, joint degeneration, and disease progression. A clear understanding of the distinct roles of BMLs and SCCs in OA is essential for the development of targeted therapeutic strategies.

BMLs and their role in OA pain

BMLs play a pivotal role in both the structural and pain aspects of OA. Their frequent co-occurrence with SCCs highlights the complex relationship between bone pathology and pain signaling in OA. Detection of BML through imaging techniques, such as magnetic resonance imaging (MRI), enables clinicians to assess disease severity and monitor the effectiveness of therapeutic interventions (6). Understanding the pathophysiology of BMLs, the mechanisms behind their formation, and their role in SCCs formation, is crucial for developing more effective pain management strategies and preventing further joint deterioration in OA (37). The clinical implications of these findings suggest that better understanding and targeting of BMLs can improve the management of patients at risk for disease progression and ultimately mitigate the need for joint replacement (43,44).

Histologically, BMLs are characterized by necrosis, fibrosis, and trabecular abnormalities, reflecting underlying pathological changes in the bone. On MRI, BMLs appear as hyperintense regions on fluid-sensitive, fat-suppressed sequences (Figure 2). Although initially termed “bone marrow edema”, the nomenclature has evolved, as research clarified that edema constitutes only a minor component of BMLs. Rather, their development is associated with both inflammatory processes and structural changes in the subchondral bone, contributing to pain and instability (43,44).

Figure 2 MRI of a 56-year-old male patient after several weeks of increased physical activity. Fluid accumulation is observed in both the medial and lateral femoral condyle. A degenerative medial meniscus tear with a slight extrusion is present. Arrows indicate the fluid accumulations. MRI, magnetic resonance imaging.

In symptomatic OA patients, BMLs are present in approximately 57% of cases, with prevalence increasing to nearly 100% in advanced OA (43,47). Additional studies have shown that BMLs are found in 77.5% of individuals with knee pain compared to only 30% in those without knee pain (48). Larger BMLs have particularly been associated with increased pain severity, likely due to elevated intraosseous pressure that compressed sensory nerves within the bone marrow. This may explain why BMLs act as chronic pain sources, often persisting until surgical interventions, such as arthroplasty-or periods of unloading are implemented. However, the presence of BMLs does not always align directly with the intensity of pain, highlighting the multifactorial nature of OA, where structural damage interacts with complex pain signaling mechanisms (43,48). BMLs are also closely tied to active bone remodeling, marked by increased markers of both bone resorption and formation. This dynamic process contributes to OA progression and is frequently associated with the development of SCCs and osteonecrosis. Areas of trabecular bone adjacent to these lesions often exhibit necrosis and ongoing bone remodeling, highlighting shared pathological pathways between BMLs and SCCs (44).

In conclusion, BMLs play a pivotal role in both the structural and pain aspects of OA. Their prevalence, association with SCCs, and contribution to pain severity make them critical targets for early therapeutic interventions. Understanding the mechanisms behind BML formation and persistence is essential for developing strategies to slow OA progression and improve clinical outcomes, reducing the need for invasive procedures such as joint replacement.

SCCs and their role on painful knee OA

SCCs are fluid-filled lesions within the subchondral bone that develop in response to joint degeneration and mechanical stress. Frequently associated with advanced stages of OA, SSCs signify severe structural joint changes. They compromise the integrity of the subchondral bone, disrupt load distribution, and accelerate joint degeneration, often correlating with worse clinical outcomes compared to knees with only BMLs or those without either condition. Their presence increases the likelihood of requiring surgical interventions, such as knee joint replacement, and they are strongly linked to progressive cartilage loss, making them important markers for disease progression (4).

Advanced imaging and histological analysis are essential to further understand the pathophysiology of SCCs. On MRI, SCCs typically appear as well-defined areas of high signal intensity on T2-weighted scans, corresponding to cystic lesions filled with necrotic bone fragments and fibrous tissue (49). This combination of diagnostic techniques provides valuable insights into the pathogenesis and progression of BML and SCCs and helps differentiate them from other bone lesions such as osteochondral defects or fractures (49).

There are several theories why SSC develop. The Synovial Fluid Intrusion Theory states that cysts develop when synovial fluid enters the subchondral bone through breaches in the articular cartilage, increasing intra-osseous pressure and facilitating cyst formation (50,51). However, SCCs can also form independently of full-thickness cartilage loss. The Bony Contusion Theory attributes their formation to microfractures and necrosis in the subchondral bone caused by mechanical overload (52-54). BMLs are frequently observed alongside SCCs, with BMLs often acting as early precursors to cyst formation (4,44,54).

Further insights are offered by the Bone Remodeling and Mechanical Stress Theory, which suggests that SCCs arise because of increased mechanical stress, which triggers microdamage in the subchondral bone. This damage initiates a cascade of biological responses, including osteoclast activation and bone resorption, leading to cyst formation, particularly in areas where the cartilage is already compromised (43). The concept of Bone-Cartilage Crosstalk is also pivotal in the development of SCCs, as disruptions in molecular signaling pathways involving transforming growth factor-beta and BMPs, which play critical roles in both bone remodeling and cartilage health, can lead to cartilage degeneration and the formation of SCCs (43).

Inflammation also plays a significant role in the pathophysiology of SCCs. Elevated levels of inflammatory mediators such as prostaglandin E2 and interleukins 1 and 6 in cystic lesions stimulate osteoclast activation and bone resorption, exacerbating SCC formation. This Internal Inflammatory Theory suggests a synergistic effect of local inflammation combined with mechanical stress in SCC formation (6). Neurogenic factors like NGF may additionally enhance pain associated with SCCs by sensitizing nociceptive pathways, thereby amplifying pain perception in OA patients (43).

Neuropathy in bone and OA pain: entering a vicious cycle

Lastly, pain in OA arises not only from mechanical damage and inflammation of joint tissues but also from neuropathic mechanisms. While traditional models of OA pain have focused on peripheral pain mechanisms, which involve the activation of primary nociceptors in somatic tissues, there is increasing evidence suggesting that neuropathic pain contributes significantly to the overall pain burden. Neuropathy in the subchondral bone, as well as in the synovium and other joint tissues, can result from injury or degeneration of peripheral sensory nerves, leading to a heightened and more persistent pain response (45). Animal studies have demonstrated peripheral nerve injury in OA, revealing increased markers of neuropathic pain such as dorsal root ganglion immunoreactivity and spinal microglial activation in response to joint degeneration. These findings suggest that nerve damage in the subchondral bone and surrounding tissues contributes significantly to pain signaling, marking a peripheral neuropathy component in OA pain (45,46).

The presence of neuropathy in OA is associated with more severe pain, greater disability, and a diminished quality of life compared to patients without neuropathic pain. This underscores the importance of addressing neuropathic mechanisms in pain management (45). Traditional analgesics often fail to provide relief for patients suffering from this type of pain, prompting a shift toward therapies targeting neuropathic pain mechanisms. In this context, anticonvulsant drugs, typically used to manage neuropathic pain, have shown efficacy in alleviating OA pain, suggesting that targeting neuropathic pain pathways may offer new therapeutic strategies (46).

An increasing body of evidence highlights the role of neuropathy as a key driver of chronic pain in OA, rather than a secondary consequence of joint degeneration. Among emerging therapeutic strategies, inhibitors of NGF have shown particular promise in targeting neurogenic pain pathways. NGF is a potent mediator of pain sensitization, promoting both peripheral and central neuronal hyperexcitability and pathological nerve sprouting in areas of joint inflammation (55). Elevated NGF levels have been consistently identified in the synovium of patients with painful OA, reinforcing its relevance to disease-related pain (56). Monoclonal antibodies directed against NGF, such as tanezumab and fasinumab, have demonstrated superior efficacy in clinical trials compared to placebo and, in some cases, to nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids—especially in patients with moderate-to-severe OA pain who do not respond adequately to standard analgesics (57). However, the enthusiasm surrounding these agents has been tempered by safety concerns, most notably the emergence of rapidly progressive osteoarthritis (RPOA), which has led to restrictions in their clinical use and delayed regulatory approval in both Europe and the United States (58).

Despite these challenges, NGF inhibitors remain a compelling therapeutic avenue. Their targeted mechanism offers a much-needed alternative for patients suffering from debilitating OA pain, particularly those with a neuropathic component. Moving forward, a deeper understanding of the mechanisms underlying nerve injury, sensitization, and degeneration in subchondral bone and other joint tissues will be crucial. Ultimately, a comprehensive treatment paradigm that addresses both nociceptive and neuropathic elements of OA pain is likely to provide the most effective and durable relief for affected individuals.

Conclusions

The subchondral bone plays a critical yet often underappreciated role in maintaining joint health, influencing the success of osteochondral repair, and contributing to the progression of OA. Emerging evidence underscores the importance of preserving subchondral bone integrity during joint-preserving surgeries, as its condition is fundamental to achieving optimal repair outcomes. In OA, the contribution of neuropathic pain requires greater consideration, with targeted therapies and medications offering potential avenues for improved pain management. A comprehensive understanding of the complex interplay between subchondral bone and cartilage health is vital for improving the treatment of OA and cartilage injuries. As translational research advances, future studies should focus on tailored strategies. Particular emphasis should be placed on targeted therapies for the subchondral bone. This integrated perspective promises to refine current treatment strategies and lead to more effective, long-lasting solutions in osteochondral repair and OA management.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Joint, for the series “Current Concepts and Techniques in Soft Tissue Repair and Joint Preservation”. The article has undergone external peer review.

Peer Review File: Available at https://aoj.amegroups.com/article/view/10.21037/aoj-25-12/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoj.amegroups.com/article/view/10.21037/aoj-25-12/coif). The series “Current Concepts and Techniques in Soft Tissue Repair and Joint Preservation” was commissioned by the editorial office without any funding or sponsorship. T.C. served as the unpaid Guest Editor of the series. T.C. receives grant support from the Rudin Foundation, educational support from Arthrex, MidAtlantic Systems, and Smith & Nephew. T.C. holds inventorship on two prior patents at the Hospital for Special Surgery, serves as a member of the AOSSM Research Committee, and holds a leadership role at ORS. Additionally, T.C. has ownership and board positions at Sustain Surgical Inc. and Kondral Tech Inc. J.L. has received research support from Amgen and Radius and consulting fees from Lenoss, Amgen, Mesentech, and Merck. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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