Abstract
Osteoarthritis (OA) is a degenerative joint disorder in which progressive articular cartilage loss occurs alongside pathological changes in subchondral bone and other joint tissues. The pathophysiological role of bone in OA has been a point of interest for many years and has resurfaced again in recent years as a potential target for new treatments. Articular cartilage and subchondral bone together form the osteochondral unit. Its homeostasis and integrity are reliant on biochemical crosstalk and biomechanical interplay between the two. Subchondral bone, with its relatively greater stiffness and strength, provides mechanical support to the overlying cartilage and absorbs much of the mechanical force transmitted through the joint. Mechanical instability in osteoarthritic joints is thought to be a significant risk-factor in joint disease, due to the mechano-sensitive nature of many of its native tissues. Although the progression of joint disease remains incompletely understood, significant changes in subchondral bone remodelling, structure, composition, and mechanical properties have been documented in animal and human studies of OA. The purpose of this review is to explore and discuss these bony changes associated with disease and, in particular, contextualise the basic science and clinical literature on the role of subchondral bone in OA.
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Introduction
Osteoarthritis (OA), the most common degenerative joint disorder, affects more than 40 million people across Europe [1] with a 45% lifetime risk for developing symptomatic knee OA [2] and a 25% lifetime risk for developing symptomatic hip OA [3]. Although OA exhibits heterogeneous aetiologies, the radiographic loss of articular cartilage is its most common hallmark. Cartilage degeneration typically occurs in conjunction with other radiographic features, including sclerosis of subchondral bone and osteophyte formation—which are considered secondary hallmarks of the disease. OA presents clinically as joint pain and impaired function. Interventions at present are limited in their efficacy and are insufficient to stop or reverse disease progression. Thus, clinical management is limited to pain relief, conservative treatment, and, eventually, joint replacement.
The classical view of OA as a degenerative disease of cartilage alone has expanded in recent decades to recognise the involvement of other joint tissues such as subchondral bone, ligaments, menisci, entheses, and synovial tissues [4, 5]. Many of the most pronounced pathological changes occur in cartilage and subchondral bone. Together, these two components form the osteochondral unit. Its mechanical role is to sustain and distribute forces across the joint. Subchondral bone, with its relatively greater stiffness and strength, provides support to the joint and absorbs/redistributes much of the mechanical force transmitted across it [6,7,8]. To successfully achieve this, bone must maintain a dynamic structure and adapt to its mechanical environment through modifications in composition and microstructure. Moreover, these changes in bone properties may also influence cartilage homeostasis via biochemical crosstalk and biomechanical interplay. Thus, these mechano-sensitive mechanisms in subchondral bone are integral to healthy joint homeostasis but may be disrupted in osteoarthritic bone environments.
Pre-clinical and clinical studies have demonstrated that pathological changes in subchondral bone are associated with OA. In animal models, multiple strategies have been used to induce OA. These broadly fall into two categories: (i) spontaneous models and (ii) induced models (surgical, chemical, and biomechanical). An assessment of the individual merits of these models is beyond the scope of this review but can be found in the literature [9]. Briefly, the Dunkin-Hartley guinea pig is a spontaneous model of OA. Chemically induced models of OA involve the introduction of reactive agents like monoiodoacetate (MIA) which, as an alkyl halide, reacts with cysteine residues in protein to degrade cartilage. Much of the literature features models where disease is induced by creating joint instability via surgical transection of specific joint structures (e.g. medial meniscus, cruciate ligament). A subset of these models replaces invasive surgical procedures with biomechanical loading protocols that induce damage to joint structures—without surgical incision. As with all model systems, each of these has advantages and disadvantages, and while most do generate responses in subchondral bone—it is not yet clear which is most representative of the clinical condition. In patients, the chief drawback is that recruitment criteria require radiological evidence of OA, which limits studies to patients with moderate/advanced OA. Nevertheless, these pre-clinical models and clinical studies have been, and will continue to be, indispensable in exploring the role of subchondral bone in OA.
The purpose of this review is to contextualise skeletal changes associated with OA based on current basic science and clinical evidence. With this objective in mind, we propose a hypothetical model of the chronological sequence of OA-associated changes in subchondral bone (Fig. 1). In this model, mechanical perturbation of the joint due to repetitive loading or joint trauma is the stimulus for OA initiation and the formation of microdamage. Two key events ensue (i) increased remodelling at the damaged sites thereby resulting in (ii) elevated levels of transforming growth factor β1 (TGF-β1) in subchondral bone (Fig. 1). These events set in motion changes to subchondral bone structure, composition, and mechanical properties and culminate in the well-recognised radiographic features of late-stage OA. The following sections in this review are subdivided to examine in detail these changes: “Bone Remodelling,” “Bone Structure,” “Bone Composition,” “Bone Mechanics,” and “Bone–Cartilage Crosstalk”.
Hypothetical model of the sequence of subchondral bone changes associated with osteoarthritis
Bone Remodelling
Bone Remodelling and Associated Morphological Changes in OA
Pathological changes in subchondral bone remodelling in the initiation and progression of OA are distinctly biphasic and corresponds to the early and late phases of the disease [10, 11]. Studies in both animal OA models and humans have observed increased subchondral resorption in early-stage OA with associated morphological changes characteristic of osteopenia (Fig. 2). Late-stage OA, contrastingly, is characterised by increased bone formation and subchondral sclerosis (Fig. 2). Of particular significance is the finding that OA does not progress in the absence of increased remodelling in the early phases of the disease [12]. This provides a rationale for the use of anti-resorptive agents such as bisphosphonates as a potential treatment for OA, which will be discussed in more detail below.
Morphological changes in the osteochondral unit at different stages of disease progression. Early-stage OA is characterised by osteopenia with decreased subchondral cancellous bone mass and a thinner, more porous subchondral cortical plate. Late-stage OA is characterised by sclerosis with increased cancellous bone volume and a thicker cortical plate. Reprinted by permission from Springer Nature: Springer Nature, Nature Reviews Rheumatology [10], © 2012
Animal Studies
The biphasic remodelling response in OA has been demonstrated in a range of animal models [13,14,15,16,17,18,19,20,21,22]. Botter et al. reported increased osteoclast activity directly underneath the subchondral bone plate at 2 weeks following OA induction by collagenase injection in a murine model [22]. Subsequently, bone formation rate (BFR) almost doubled compared to controls in subchondral trabecular bone. Likewise, Benske et al. reported increases of 3–5-fold in the mineral apposition rate (MAR) in the knees of mice with spontaneous OA development [13]. Here, the phenomenon was localised to regions adjacent to degenerated cartilage. Subsequently, the maximal MAR decreased with OA progression [13]. In a murine anterior cruciate ligament transection (ACLT) model, Zhen et al. found subchondral bone remodelling was augmented as early as 1 week post-ACLT with large bone marrow cavities present at 4 weeks [14]. In contrast, total subchondral bone tissue volume was 20% higher at 8 weeks following surgery [14]. In a rat ACLT model, Hayami et al. observed subchondral bone resorption at 2 weeks post-surgery and then sclerosis and osteophyte formation at 10 weeks [15, 16]. Similarly, bone mineral density (BMD) was lower at 4 weeks and higher at 12 weeks in the knees of meniscectomised guinea pigs [17].
In general, the transient morphological changes accompanying the biphasic remodelling phases are similar in both subchondral cortical and cancellous sites. However, trabecular bone volumes have been found in some instances to remain osteopenic or unchanged in the late, sclerotic stages of the disease. This discrepancy may be explained by the regions of interest (ROI) considered in the analyses. Pathological changes in morphology are highly localised to sites adjacent to cartilage degradation. Both Hayami et al. and Dedrick et al. noted that these morphological changes were not present if the entirety of the epiphyseal region was included in their analyses instead of localised trabecular sites [16, 18, 19].
Biphasic subchondral bone remodelling may result from different responses by which bone and cartilage adapt to their changing mechanical environment. This differential capacity was demonstrated by Ko et al. in a non-invasive murine model [23], where knees were subjected to a single cyclic loading session, but no macroscopic joint damage. Loading induced a transient subchondral remodelling response where cancellous bone loss and thinning were observed at 1 week, and was consistent with a coincident increase in osteoclast numbers. Bone loss was reversed at 2 weeks with morphological parameters returning to baseline values. In contrast, loading induced a progressive catabolic chondrocyte response in cartilage with concomitant proteoglycan loss and localised cartilage thinning. Thus, adaptation to acute mechanical loading in bone is remarkably rapid and indeed reversible once a physiological loading state is restored. Whether there is a link between the limited capacity of chondrocytes to restore cartilage integrity and the subsequent sclerosis of subchondral bone remains unknown.
Human Studies
Several key findings relating to bone remodelling and OA have been observed in clinical studies. In a biochemical study, Mansell et al. reported bone remodelling to be increased 20-fold in retrieved OA femoral heads relative to controls [24, 25]. The rate of type I collagen synthesis was determined via C-terminal propeptide of type I collagen (PICP), while degradation was determined by matrix metalloproteinase 2 (MMP-2) activity. The increase in type I collagen synthesis was reflected by an increase in alkaline phosphatase, a bone formation marker. In a complementary study, Bettica et al. reported increased levels of bone resorption markers, namely type I collagen C-terminal and N-terminal telopeptides, in postmenopausal women with progressive OA in a longitudinal study of women aged 45–64 [12]. Importantly, this increase in bone resorption was not observed in patients with non-progressive OA.
Scintigraphy studies in humans have also demonstrated increased subchondral bone turnover with scintigraphic detection preceding radiographic evidence [26,27,28,29]. Most notably, in a study using technetium-labelled bisphosphonate, Dieppe et al. identified increased subchondral bone turnover in patients with established OA using this method [27]. Furthermore, the authors found that cartilage degeneration does not significantly progress in the absence of a concomitant change in subchondral bone turnover.
Multiple MRI studies have also highlighted the role of subchondral bone in OA progression. Reichenbach et al. reported the presence of bone attrition (i.e. altered bone contours) in the knees of early OA patients before joint space narrowing was visible radiographically [30]. Furthermore, Neogi et al. demonstrated a strong association between subchondral bone attrition and localised cartilage loss within the same sub-region in a cohort of individuals who had, or were at high risk for developing, knee OA [31]. The risk of localised cartilage loss was increased 7-fold in regions with subchondral bone attrition. Similarly, Bolbos et al. reported a correlation between loss of subchondral trabecular bone and cartilage degradation in a study of young and middle-aged OA patients (aged 29–72 years) [32].
Aberrant Activation of TGF-β
At the molecular level, the uncoupling of bone resorption from formation in OA joints is indicative of aberrations in the signalling pathways governing bone remodelling. Most notable is the transforming growth factor-beta (TGF-β) signalling pathway which is a key regulator of homeostasis for both bone and cartilage [33]. It has been identified as a key signalling pathway in the pathogenesis of OA (as illustrated in Fig. 1) [14, 33]. Unlike other cytokines, TGF-β is secreted into the extracellular matrix (ECM) of different tissues in an inactive or latent form. Its activation is achieved by precise spatiotemporal regulation and occurs in response to tissue remodelling/injury or alterations in mechanical loading. Activation of latent TGF-β in the matrix orchestrates the coupling of osteoclast and osteoblast activity. Specifically, active TGF-β1 is released during bone resorption and induces migration of mesenchymal stem cells (MSCs) to the resorption site [34]. TGF-β, in coordination with other signalling molecules and the physico-chemical properties of the exposed bone site, then stimulate the differentiation of MSCs into osteoblast lineage cells [35,36,37]. Disruption of this pathway thus has the potential to uncouple bone formation from resorption.
In OA joints, deregulation of TGF-β signalling impairs the structural and mechanical integrity of both subchondral bone [14, 33] and articular cartilage [38,39,40,41] and may contribute to the progression of OA. Indeed, OA progression has been linked with high levels of active TGF-β in subchondral bone in both human and animal studies [14]. Constitutive expression of active TGF-β1 by osteoblastic cells in transgenic mice was found to induce an osteoarthritic phenotype with abnormal subchondral bone structure and significant degeneration of articular cartilage [14, 34]. Specifically, as illustrated in Fig. 1, the elevation in TGF-β1 levels in subchondral bone has been linked to osteophyte formation (discussed in the “Bone Structure” section) and alterations in osteoblast expression and hypomineralisation (discussed in the “Bone Composition” section). Further underscoring its critical role, Zhen et al. demonstrated localised inhibition of TGF-β in subchondral bone attenuated cartilage degeneration in different murine models of osteoarthritis [14]. This intervention strategy is not without its challenges as TGF-β has distinct roles in subchondral bone and articular cartilage (as described in the “Bone–Cartilage Crosstalk” section). Thus, high concentrations of TGF-β in subchondral bone seem to initiate the cascade of pathological changes in subchondral bone, and interventions to restore TGF-β levels following acute joint injury may prevent OA development.
Bisphosphonate Therapy for OA
Therapeutic interventions to regulate bone remodelling in OA have been proposed as a treatment in the past. The rationale is based on the significance of increased remodelling in the early phase of disease progression (refer to Fig. 1) and the finding that OA does not progress in its absence [12]. Recent experimental studies have sought to test whether bisphosphonate therapy could be useful as an OA therapy. Bisphosphonates exhibit a high specificity for active sites in bone and can potently suppress remodelling activity. In pre-clinical studies, bisphosphonates have demonstrated potential in preventing or slowing the progression of bone pathology [15, 42,43,44,45,46,47]. Indeed, some studies found bisphosphonates exerted a chondroprotective effect despite there being no known direct effect on chondrocytes [15, 43,44,45]. It is also notable that efficacy in pre-clinical studies has not been consistent [48,49,50]. In patients, the translation of bisphosphonate therapy to the clinic has had limited success in randomised controlled trials (RCTs) [51,52,53,54,55,56]. These discrepancies between pre-clinical and clinical studies are multifactorial. Foremost is the recruitment of patients with radiographic or functional evidence of OA and thus may present stages too advanced for bisphosphonate therapy to be effective. Identification of patients in the early stages of OA is challenging though and may only be feasible in subjects with secondary, post-traumatic OA (PTOA).
Bone Structure
Morphological changes in subchondral bone are well documented at the microscale (Fig. 2). These changes reflect the biphasic remodelling stages of OA progression discussed above. Early OA is characterised by increased resorption with decreased subchondral bone mass and a thinner, more porous cortical plate [10, 15, 16, 20, 22, 32, 57,58,59,60,61]. Late phase OA is characterised by subchondral sclerosis which manifests as densification and thickening of the cortical plate [10, 15,16,17, 19, 22, 57, 62,63,64,65,66]. Jia et al. proposed a mechanism by which subchondral sclerosis is stimulated in murine models of severe, advanced OA [67, 68]. Using a novel μCT protocol to generate colour maps of subchondral plate thickness, the authors established that site-specific plate thickening is correlated to localised loading and to degradation of the overlying articular cartilage. Reduced levels of sclerostin, an inhibitor of bone formation, were also observed in conjunction with cortical plate thickening. Expression of sclerostin by osteocytes is mechano-regulated, and this study demonstrated that sclerostin was downregulated by abnormal loading. Here, the authors suggest that subchondral bone sclerosis is a secondary consequence of cartilage degeneration and is induced by mechanically mediated downregulation of sclerostin. Wu et al. further corroborated this finding in their observation that sclerostin levels within the subchondral bone plate in OA patients negatively correlated with OA severity [69]. Coincident with their observation of reduced sclerostin expression was the activation of the Wnt/β-catenin signalling pathway, thus increasing osteogenesis and inhibiting bone resorption.
In addition to these remodelling-induced morphological changes, osteoarthritic subchondral bone shows evidence of pathological features including (i) microdamage, (ii) bone marrow lesions (BMLs), and (iii) osteophytes.
Microdamage
Physiological loading of bone is known to routinely cause the formation of microdamage. In healthy tissue, repair of microdamage is orchestrated by osteocytes and carried out by basic multicellular units (BMUs) [70]. With ageing, disease, and treatment, this process may be compromised and microdamage can accumulate [71]. The consequences of microdamage accumulation are both mechanical and biological. Mechanically, structural integrity is compromised and fracture risk increased. In fact, microdamage accumulation in the range of 1–2% (volume fraction) can reduce strength by 50–60% [72,73,74,75,76,77]. Biologically, the accumulation of microdamage elicits damage responses. Osteocytes in the vicinity of microdamage undergo apoptosis which, in turn, initiates osteoclast-mediated remodelling via increased production of RANKL which stimulates osteoclastogenesis [78].
Much of the current understanding of microdamage-associated remodelling is derived from experimental studies of diaphyseal cortical or trabecular bone sites [79,80,81]. Microdamage in subchondral bone appears to produce similar responses (Fig. 1) but its significance in joint disease and failure remains unknown [82,83,84,85]. Ramme et al. demonstrated the co-localisation of microdamage with subchondral remodelling following ACL rupture in a rodent model [86]. Clinically, the presence of subchondral microdamage following acute joint injury has not yet been demonstrated. However, BMLs, which have been associated with subchondral microdamage, are regularly observed on MRIs following clinical knee injury [87, 88]. Subchondral microdamage may thus have a significant role in OA (and particularly PTOA) initiation but this remains to be explored and fully characterised.
Bone Marrow Lesions
In recent years, BMLs have been recognised as an integral feature in acute joint injury [72]. It has been proposed that they are involved in the development of PTOA. However, this potential relationship is not well understood. BMLs are ill-defined regions of hyperintense signal in fluid-sensitive, fat-suppressed MR images [89]. Histological analyses of BML biopsies from patients undergoing joint arthroplasty have revealed the accumulation of microfractures at different stages of healing, bone marrow fibrosis, bleeding, oedema, and necrosis [90,91,92,93]. BMLs are likely induced by mechanical overload during joint trauma (Fig. 1). Observations in support of this include their presence following an acute ACL injury in 80–98% of patients [94,95,96] and the localisation of BMLs within a joint to sites of mechanical damage [93, 97]. Thus, microdamage accumulation may constitute a mechanism by which BMLs form (Fig. 1). Intriguingly, it has been proposed that microdamage accumulation may initiate a reparative response with localised inflammatory events, and BMLs may represent an impaired fracture repair process [98]. Immune cells have significant roles in fracture repair and there may exist a distinct osteoimmunological link, potentially via the OPG/RANKL system [98,99,100]. In addition, TGF-β1 may also have a role in BML formation based on the observation of osteoid islets forming in the subchondral bone marrow in response to aberrant activation of TGF-β1 in mice (Fig. 1) [14].
BMLs are clinically relevant as their presence increases the risk for structural degeneration of articular cartilage [93, 101], development of knee pain [53, 102,103,104], and disease progression [93, 105,106,107,108,109]. Furthermore, they are linked with the development of cysts and have been proposed as early pre-cystic lesions (Fig. 1) [110, 111]. Intriguingly, BMLs have been found to be strongly indicative of disease severity [93, 108] and have been proposed as potent predictors of disease progression. Libicher et al. reported that BMLs preceded cartilage degeneration in an MRI study using an ACLT canine model [112]. Clinically, the presence of BMLs has been documented in asymptomatic patients and may be predictive of an increased risk for OA [106, 113,114,115]. BMLs have also been documented in patients with symptomatic early-stage OA and in patients with severe late-stage OA [93, 101, 103, 105, 113, 116]. Observations in asymptomatic or early OA subjects found that BMLs may decrease in size or resolve completely [101, 109, 117]. Conversely, BMLs were likely to persist and enlarge in size in subjects with progressive OA [93]. Indeed, Laslett et al. reported that decreased BML size was concomitant with reduced knee pain in patients treated with Zoledronate [53].
Formation of Osteophytes
Osteophytes are another pathological feature of OA and are outgrowths of cartilage which subsequently undergo ossification [118, 119]. Their presence in radiographs is a significant criterion in the diagnosis of disease. Osteophyte formation normally occurs at the joint margins and outgrowths in central regions of the articular space present in approximately 15% of patients [120]. Osteophyte formation follows the prenatal bone development pathway with chondrogenic differentiation of MSCs resulting in cartilaginous outgrowths [118, 121]. Subsequently, these ossify via a combination of endochondral and intramembranous ossification [119, 122]. Their formation culminates in structures extending from the joint margins which are integrated with the native bone and covered by cartilage [118, 119].
Osteophytes are regarded as pathological adaptations in response to joint instability. The role of the mechanical environment has been demonstrated in animal studies where osteophyte growth was stimulated with exercise and inhibited by immobilisation [123,124,125,126,127]. Hsia et al. found osteophyte formation following ACL rupture in a murine model coincided with joint restabilisation and reduced range of motion [128]. Likewise, Pottenger et al. found that the removal of marginal osteophytes in patients with primary knee OA increased joint motion and concluded that osteophytes act as mechanical stabilisers in osteoarthritic knees [129]. In agreement, Murata et al. reported that restoration of physiological joint kinematics following ACL transection in a rat model inhibited osteophyte growth [130]. Noteworthy also is the role of aberrant TGF-β/BMP signalling in osteophyte formation with TGF-β1 and BMP-2 identified as potent inducers (Fig. 1) [131,132,133].
Bone Composition
Homotrimeric Collagen
Type I collagen is the principal organic constituent of bone and confers the tissue with tensile strength and toughness [134, 135]. In its dominant isoform, type I collagen is a heterotrimeric triple helix composed of two α1 chains and one α2 chain. However, its normal phenotypic expression by osteoblasts is altered in OA bone with increased secretion of a homotrimeric isoform of type I collagen composed of three α1 chains [136]. The homotrimeric isoform of type I collagen has previously been found in foetal tissues, fibrosis, and cancer in humans albeit with genetically distinct α1 chains [137]. In contrast, the homotrimeric isoform present in OA bone is characterised by an excess of α1 chains substituting the α2 chains [136]. This homotrimeric phenotype is also naturally expressed in the murine model of osteogenesis imperfecta (oim), a genetic brittle bone disease, resulting in spontaneous skeletal fractures [138]. However, the mechanical consequences of homotrimeric type I collagen specific to OA are, as yet, unclear. Indeed, Couchourel et al. observed collagen to be hypomineralised in an in vitro characterisation study of OA osteoblasts but this does not appear to translate to an increased susceptibility to fracture at the whole bone level [139].
The mechanisms responsible for this abnormal osteoblast phenotype in OA have been partly discerned but much remains unknown. In vitro studies of OA osteoblasts found increased levels of TGF-β1expression [139,140,141]. Couchourel et al. proposed that elevated TGF-β1 levels were responsible, in part, for increased expression of α1 chains in OA subchondral bone (Fig. 1) [139]. TGF-β1 is known to inhibit mineralisation in vitro either directly or via BMP-2 stimulated mineralisation [139]. The significant role of TGF-β1 in altered OA osteoblastic function was substantiated when its inhibition in osteoblasts was found to reduce the α1-to-α2 ratio [139]. Subsequently, Chan et al. found elevated expression of TGF-β1 stimulated expression of the Dickkopf-2 protein (DKK2) in OA osteoblasts (Fig. 1) [142]. DKK2 is an antagonist of the Wnt signalling pathway which has a critical role in osteogenesis and the regulation of terminal osteoblast differentiation. Indeed, inhibition of either TGF-β or DKK2 expression restored phenotypic expression of OA osteoblasts (Fig. 1) [142].
Hypomineralisation
Hypomineralisation of subchondral bone has been consistently reported in in vitro and ex vivo studies of OA joints. Mansell et al. conducted biochemical characterisation of OA femoral heads and showed collagen I synthesis to be augmented but with significantly reduced calcium-to-collagen ratios [24]. Similarly, Li et al. presented comparisons of material density, which is a reflection of tissue mineralisation, in cortical and cancellous subchondral bone from OA femoral heads [143, 144]. OA bone exhibited significantly reduced material density indicative of hypomineralisation at both cortical and cancellous sites, and this finding was further corroborated by a significant decrease in mineral content as measured by gravimetric analyses. Density fractionation measurements of cortical and cancellous samples from the same site by Grynpas et al. also found hypomineralisation in osteoarthritic bone [62]. Similarly, Ferguson et al. found mineralisation, as determined by scanning electron microscopy using backscattered electrons (qBSE), to be significantly lower at the same site [145]. Moreover, in a complementary study, Li et al. found this state of hypomineralisation in OA hip joints extended to the trabeculae of the femoral neck [146].
Notably, the cumulative data from these studies suggest that proximity to the cartilage surface influences the degree of hypomineralisation with the effect most pronounced at skeletal sites adjacent to the joint [24, 62, 143, 144, 146]. Cox et al. quantified the depth-dependency of mineralisation in osteochondral plugs harvested from the proximal tibiae of OA patients presenting different stages of the disease [147]. Mineralisation was found to be lowest in samples with the highest severity of cartilage degeneration. Hypomineralisation varied from 6% at subchondral sites at a depth of 1 mm from the cartilage to 4% at subchondral sites at a depth of 3 mm from the cartilage. Thus, there exists a relationship at a highly localised level between bone mineralisation and cartilage degeneration.
Moreover, Zuo et al. presented comparisons of mineral distribution in the subchondral cortical and cancellous regions of the proximal tibia in samples classified as either Grade I or Grade IV [148]. Mineralisation, as characterised by BSE, was observed to progress from homogeneous distribution in cortical/cancellous regions in grade I samples to a heterogeneous distribution with concentrated areas of high mineralisation in grade 4 samples (Fig. 1).
Alterations in mineralisation are primarily a consequence of alterations in bone remodelling. Specifically, increased remodelling inhibits mineral accretion in newly formed bone and yields hypomineralised bone. Moreover, hypomineralisation was also observed by Couchourel et al. in their in vitro characterisation study of OA osteoblasts [139]. Thus, this deficit in mineralisation is potentially exacerbated by the presence of both (i) the homotrimeric collagen phenotype and (ii) elevated production of both TGF-β1 and Dickkopf related protein 2 (DKK2) in OA subchondral bone (Fig. 1). Indeed, mineralisation by BMP-2, an anabolic agent, is less potent in subchondral bone due to elevations in either TGF-β1 or DKK2 expression [139, 142]. Samples in all the above studies were harvested prior to arthroplasty and therefore are representative of moderate or late phase OA. Thus, it is conceivable that subchondral bone in OA attains a hypomineralised state early in OA progression and this state is not remedied by the reduced bone turnover in late phase OA.
Noteworthy also, is the frequently reported association between OA and an increase in BMD at both the affected joint and the appendicular skeleton in clinical literature [149,150,151,152,153,154]. However, it is important to note that BMD, as measured by dual energy x-ray absorptiometry (DEXA), reflects bone quantity and is not a measure of the material density of the bone itself. Therefore, an increase in BMD can be consistent with the sclerotic response of bone in the advanced stages of OA.
Bone Mechanics
OA bone is generally characterised by a decrease in intrinsic tissue properties and an ensuing adaptive response that results in an increase in extrinsic bone tissue mechanical properties. Literature on the mechanical properties of subchondral bone presents either (i) intrinsic or material properties, constituting a measure of the mechanical properties independent of bone size and structure, or (ii) extrinsic or apparent properties, representing the properties of the bone structure in its entirety. This is an important distinction in interpreting the literature and an in-depth review can be found elsewhere [155].
Intrinsic Properties: Elastic Modulus
Both cortical and cancellous sites in OA bone are reported to exhibit decreased elastic moduli across different length scales. Day et al. reported a 60% decrease in the elastic modulus of subchondral trabeculae in the proximal tibia of individuals with mild cartilage degeneration [156]. The authors used a combination of finite element (FE) modelling, μCT imaging, and compression mechanical testing in determining the elastic moduli. Similarly, the elastic moduli of subchondral cortical bone, as determined by ultrasound measurements, were found to be decreased in the femoral heads of OA subjects [143]. In contrast, Hargrave-Thomas et al. found no significant differences in the elastic moduli of the cortical plate of bovine patellae at the macroscale and microscale using three-point bending and microindentation respectively [157].
More recent studies have reported elastic moduli obtained at the nanoscale using nanoindentation techniques. Pragnère et al. found a 16% decrease in the elastic moduli of the cortical plate at 6 weeks following OA induction in a PTOA rabbit model [158]. Of considerable interest in their results was the existence of a more pronounced stiffness gradient between cartilage and subchondral bone as a result of OA induction. Stiffness values decreased by 42% and 37% in hyaline cartilage and calcified cartilage respectively compared with only 16% in the cortical plate.
Also noteworthy in the literature is the finding that the elastic modulus at the nanoscale initially decreases with the onset of OA and subsequently appears to regain baseline values at later stages. Hargrave-Thomas et al. found elastic moduli in the cortical plate of bovine patellae to significantly decrease in samples with mild cartilage degeneration only to then recover in samples presenting moderate cartilage degeneration [157]. Zuo et al. also reported similar results in comparisons of Grade I and Grade IV human proximal tibial trabeculae with increases in the reduced modulus (Er, a measure of both sample and indenter compliance) of 19% and 25% at trabecular osteon and lamellar sites respectively [148]. Moreover, Ferguson et al. found no significant differences in elastic moduli in the cortical plate of human femoral heads between end-stage OA and normal post mortem samples [145].
The stiffness of mineralised tissues is strongly influenced by their degree of mineralisation [159, 160]. Thus, lower stiffness values in these samples are consistent with the hypomineralised nature of OA bone. Moreover, the apparent recovery of bone stiffness at the nanoscale with late phase OA progression is likely a consequence of the sensitivity of nanoindentation to the heterogeneous distribution or aggregation of mineral crystals with late phase disease progression [148].
Much has been written and postulated on the significance of subchondral bone stiffness in the initiation and progression of OA. Notably, in the 1970s and 1980s, Radin et al. proposed the hypothesis that initiation and progression of cartilage degradation were induced by an increase in the elastic modulus of the subchondral bone and resulting in a stiffness gradient between the bone and the overlying articular cartilage [161, 162]. Although prescient for its time, the absence of substantive evidence in the intervening decades has necessitated re-evaluation of this premise. Furthermore, subchondral bone plate stiffness has been reported to be lower in the explanted femoral heads of individuals with either osteoporosis (OP) or OA [143]. This suggests that lower stiffness of the subchondral bone plate cannot, in itself, account for the preservation of the overlying cartilage in the OP samples nor explain its destruction in the OA samples.
Extrinsic Properties
In general, measures of extrinsic or apparent bone mechanical properties are augmented with disease progression. Li et al. conducted unconfined compression testing of subchondral trabeculae samples from OA femoral heads and reported increased stiffness and energy absorbed to yield parameters [144, 163]. However, there are also exceptions to this in the literature wherein no demonstrable change in extrinsic mechanical properties is present [164, 165].
Increased mechanical strength/stiffness might seem paradoxical in light of the documented hypomineralisation of subchondral OA bone but it can be understood in the context of coincident pathological changes. For example, Li et al. showed that subchondral trabecular bone volume was 60% greater in OA subjects [144]. This increase in bone volume fraction characteristic of late phase OA could be an adaptive response to the increased bone strain that is a consequence of hypomineralisation in bone. Day et al. constructed models of subchondral trabecular bone using high-resolution μCT imaging to simulate mechano-regulated bone adaptation in response to the degeneration of intrinsic bone mechanical properties [155]. Using their strain-driven model, the authors demonstrated that a decrease in intrinsic bone stiffness necessitated an increase in bone volume fraction to compensate. Namely, the authors reported that a reduction of 20% in intrinsic bone stiffness resulted in an increase of 25% in the extrinsic stiffness. Thus, their model is supportive of the idea that subchondral stiffening is a necessary compensatory mechanism to counteract the greater compliance of OA bone.
Bone–Cartilage Crosstalk
Pathological changes associated with OA are evident in both cartilage and subchondral bone, and it has stimulated interest in the potential signalling or crosstalk mechanisms between the two tissues. A brief commentary is presented here, but comprehensive reviews on the subject can be found elsewhere [166,167,168].
Several studies have documented evidence for the feasibility of bone–cartilage crosstalk across the osteochondral junction [22, 169,170,171]. Pan et al. demonstrated the diffusion of small molecules between the bone marrow and articular space using fluorescent tracer molecules in mouse joints [169]. Histological analyses of the osteochondral interface by Imhof et al. detailed the dense subchondral vasculature which permits communication between the tissues [171]. Furthermore, studies have suggested that crosstalk is enhanced with OA progression. Hwang et al. reported increased fluid flow conductance in human osteochondral plugs in association with OA severity [172]. Increased porosity of the subchondral plate has also been documented with OA progression and has been attributed to increased osteoclast activity [22, 172, 173]. Moreover, these increases in plate porosity and remodelling activity seem to subsequently permit a vascular invasion of the cartilage [22, 172, 174]. Formation of microcracks/fissures in response to abnormal loading in OA joints may also function as transport conduits between cartilage and bone [167].
Accumulating evidence also supports the existence of molecular interactions between the two compartments [166, 167, 175, 176]. The TGF-β and Wnt/β-catenin signalling pathways have critical regulatory roles in maintaining the integrity of the osteochondral unit. We have previously described OA-induced aberrations in TGF-β (as discussed in the “Bone Remodelling” section) and Wnt/β-catenin (as discussed in the “Bone Structure” section) signalling in subchondral bone. In cartilage, TGF-β-mediated signalling has an important regulatory role in maintaining its structural integrity and mechanical function [38, 41, 177,178,179]. Suppression of TGF-β signalling in cartilage has been found to aggravate cartilage degeneration and impair cartilage repair in osteoarthritic murine models [40, 133, 180]. Indeed, TGF-β has been found to be almost absent in OA cartilage compared with the high levels at which it is expressed in healthy cartilage [39]. This is in contrast to the high levels of TGF-β present in OA subchondral bone. Thus, aberrations in TGF-β levels are present in both tissues with OA progression. Notably, inhibition of TGF-β activity in subchondral bone attenuates OA progression in both tissues and further underscores their interdependence.
Interventions in the articular cartilage can similarly rescue both tissues of the osteochondral unit. Wnt/β-catenin signalling molecules have important roles in regulating the function of articular chondrocytes. Wnt antagonists such as DKK1 and sclerostin have been suggested as potential therapeutic targets as the pathway is strongly associated with OA [166, 167, 181, 182]. Oh et al. demonstrated overexpression of DKK1 in the articular cartilage of a murine OA model significantly inhibited cartilage degradation, osteophyte formation, and sclerosis in subchondral bone [181]. Thus, bone-cartilage crosstalk presents opportunities for therapeutic interventions to arrest or slow disease progression.
Conclusion
Cumulatively, the discussions presented here underscore the role of subchondral bone in OA pathogenesis and progression. To summarise these changes, we refer back to the hypothetical model of disease progression proposed in Fig. 1.
In this model, mechanical perturbation of the joint due to repetitive loading or joint trauma is the stimulus for the formation of microdamage. Increased remodelling ensues and induces resorptive changes in subchondral bone structures and elevated TGF-β1 levels in subchondral bone. Subchondral bone becomes hypomineralised as increased remodelling and the elevation in TGF-β1 hinders the accretion of mineral in the newly formed bone. Moreover, the elevation in TGF-β1 stimulates the formation of osteophytes and alters osteoblast expression with the secretion of a homotrimeric isoform of type I collagen. Together, the changes in collagen structure and hypomineralisation contribute to a lower tissue modulus. Concomitant with these changes is the formation of BMLs. Continued normal loading of the joint subsequently downregulates sclerostin expression and stimulates the sclerotic phenotype characteristic of late-stage OA.
Collectively, the sequence of events presented in this model serves to underscore the extent and variety of changes that are possible in subchondral bone during disease progression. Furthermore, it suggests that a complete understanding of all aspects of this system will be necessary to develop interventions to cease or reverse disease progression.
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Mathavan, N., Kennedy, O.D. Skeletal Changes Associated with Osteoarthritis. Clinic Rev Bone Miner Metab 17, 123–137 (2019). https://doi.org/10.1007/s12018-019-09264-0
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DOI: https://doi.org/10.1007/s12018-019-09264-0