Osteoarthritis pathophysiology: similarities and dissimilarities with other rheumatological diseases and the role of subchondral bone






Gabriel HERRERO-BEAUMONT,MD
Jorge A. ROMAN-BLAS,MD
Bone and Joint Research Unit Rheumatology Service
IIS Fundación Jiménez Díaz Universidad Autónoma
Madrid, SPAIN

Osteoarthritis pathophysiology: similarities and dissimilarities with other rheumatological diseases and the role of subchondral bone


by J . A. Roman-Blas
and G. Herrero-Beaumont ,
Spain



Osteoarthritis (OA) is a disease not only of the cartilage, but also of the whole joint. In osteoarthritis and chronic inflammatory arthritides, the intensity of the inflammatory response of the joint determines juxtaarticular bone loss. Thus, in rheumatoid arthritis, the intense synovial and cartilage inflammation, pannus formation, and systemic bone loss induce increased subchondral bone turnover with subsequent juxta-articular bone loss. By contrast, the mild and patchy synovitis seen in osteoarthritis results in lower subchondral bone turnover and less subsequent bone loss than in rheumatoid arthritis–like conditions. Angiogenesis and sensory nerve growth also contribute to joint damage to different extents in these arthropathies. However, the main underlying pathogenic mechanisms may be common among these joint diseases. A better understanding of the biological events involved in inflammation-induced bone loss in these diseases could lead to the identification of novel therapeutic strategies for the prevention of bone loss and also potentially progression of joint damage.

Medicographia. 2013;35:158-163 (see French abstract on page 163)



Osteoarthritis (OA) is a multifactorial disease that affects not only articular cartilage, but also the whole joint. The involvement of subchondral bone in OA is of great relevance and interest, as are changes that occur in the synovial membrane, tidemarks, and periarticular structures in the course of the disease.1,2 Thus, acquired or genetically conditioned biomechanical and biochemical alterations affecting any joint tissue may cause anomalous intra-articular stresses and subsequent tissue damage associated with a failure of repair.3 OA is characterized by pain, stiffness, and functional impairment ultimately resulting in chronic disability and significant economic burden, especially in the elderly.

Subchondral bone

The bone underlying joint cartilage is composed of several specific anatomical regions, including the subchondral cortical plate, subchondral trabecular bone, and subarticular bone.4 Each region is likely to contribute to cartilage pathology in a distinct manner. Current imaging techniques show unclear anatomical boundaries between these tissues, generating some confusion with regard to their study.5 Bone at the joint margins is markedly active and is frequently the site of osteophyte development in primary OA or bone erosion in inflammatory arthritis. The close relationship between subchondral bone and joint cartilage, two tissues that are adjacent to one another as well as mechanically and biologically intertwined, makes them a function- al unit that contributes significantly to normal joint function. Changes to either the mechanical or biological properties of subchondral bone may alter the corresponding state of articular cartilage, and vice versa.6 When both tissues are damaged, the relationship between them changes, thereby posing an asyet-unanswered question that has valuable therapeutic implications in the setting of chronic joint diseases.

Effect of systemic osteoporosis on subchondral bone structure and remodeling

Systemic osteoporosis (OP) alters the microstructural and biological properties of subchondral bone. Compared with normal and osteoarthritic femoral heads, the femoral heads of patients with OP show the least stiff and dense subchondral bone plates (OA femoral heads show values in between normal and OP femoral heads). Although osteoporotic bone has been found to contain less mineral, its organic and water contents have been found to be proportionally higher, suggesting no change in the relative amount of organic matrix.7 Studies in different animal models have reported that OP has a negative effect on subchondral bone integrity.8-10 In an experimental model of OP in rabbits, which was induced by glucocorticoid administration and ovariectomy, subchondral bone mineral density was significantly lower compared with controls.8 This experimental model also showed a decrease in subchondral plate thickness and only a negative tendency in bone area fraction and trabecular thickness values, while the microarchitecture index fractal dimension was increased. The decrease in subchondral plate thickness would indicate that this experimental model of OP exhibits a much more profound effect on subchondral cortical bone than subchondral trabecular bone. Increased remodeling in favor of subchondral bone resorption has also been reported in osteoporotic rabbits, as determined by reduced alkaline phosphatase expression and increased matrix metalloproteinase (MMP)–9 expression, also supported by a decrease in the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) ratio comparedwith healthy controls.9 In ovariectomized sheep, bone volume fraction was found to be reduced in subchondral bone compared with controls. Trabeculae were also significantly thinner in these animals, with reduced connectivity density, and significant alterations observed in the trabecular architecture under the tibial plateau following 12 months of estrogen deficiency.10 Lastly, in an ovariectomized mouse model, use of either estrogen supplementation or bisphosphonate treatment resulted in inhibition of tibial and patellar subchondral cortical thinning.11 Taken together, these studies demonstrate a relevant and negative effect of systemic OP on the structure and metabolism of subchondral bone.




Influence of osteoporosis in the remodeling of subchondral bone in osteoarthritis

It is increasingly acknowledged that articular cartilage homeostasis is dependent on the integrity of the underlying bone.12-15 Several studies have identified specific changes that occur to the architecture and turnover of subchondral bone in OA.16,17 The study of the influence of OP on subchondral bone remodeling could reveal relevant mechanisms involved in the development of OA. Thus, our group developed a rabbit model of surgically-induced OA preceded by OP, and demonstrated that microstructure impairment in subchondral bone associated with increased remodeling increases cartilage damage.9 Indeed, compared with control and OA knees, OPOA knees demonstrated diminished subchondral bone area/tissue area, trabecular thickness, and polar moment of inertia, as well as a pronounced decline in subchondral plate thickness. Compared with controls, the subchondral bone of OA, OP, and OPOA knees showed a decrease in alkaline phosphatase expression and OPG/RANKL ratio as well as an increase in the fractal dimension and MMP-9 expression. In addition, the severity of cartilage damage was increased in OPOA knees versus controls. Remarkably, good correlations were observed between structural and remodeling parameters in subchondral bone, and furthermore, between subchondral structural parameters and cartilage Mankin score.

In line with our results, a decrease in subchondral plate thickness was also reported in an ovariectomized murine model of intra-articular iodoacetate-induced knee OA,11 as well as in experimental models of OA evaluating the early disease stage.13,14,18-20 Thinning and porosity of the subchondral plate were only present in the medial compartment and were related to superjacent cartilage damage, while in the canine anterior cruciate ligament transection (ACLT)–medial meniscectomy model of OA,20 trabecular bone changes were mostly found in the lateral compartment and were related to mechanical unloading. Thickening of the subchondral plate has, however, been described in animal models of surgically-induced OA corresponding to late-stage disease.13,19,21 Remarkably, in some of these studies, the early decrease in subchondral plate thickness was followed by late plate thickening.13,19 Furthermore, in the rat ACLT and meniscectomy models of OA, increased mRNA levels of cathepsin K and tartrate-resistant acid phosphatase were found in subchondral bone at week 2 post surgery, as well as invasion of cathepsin K+ osteoclasts into the articular cartilage from the subchondral region. These events thus confirm that bone resorption is an early event in the disease course of OA. Up regulation of the osteoanabolic mark- ers runx2 and osterix was observed from week 4 to 6 post surgery, which is thought to constitute the pathophysiological basis for late events in the disease course of OA such as subchondral sclerosis and osteophyte formation. Local and temporal regulation of matrix degradation, differentiation, and vascular invasion markers was seen in articular cartilage in a manner consistent with the aforementioned changes in subchondral bone.22

In human knee OA, cartilage damage is frequently associated with thickening of the subchondral plate and osteophyte development.16,23 Aside from this hypertrophic OA, some authors consider that there is another variant, the atrophic form, which is characterized by a lack of osteophytes and loss of subchondral bone volume in OA patients with compromised hip and knee.24 This atrophic form probably shares several etiopathogenic mechanisms and phenotypic features with OA associated with OP (Table). Furthermore, the correlation observed in hypertrophic OA between serum levels of C-propeptide and type II collagenase has been found to be lost in atrophic OA, the latter showing reduced type II collagen synthesis.25 This could contribute to the absence of osteophyte formation as well as the increased subchondral bone turnover seen in rapidly progressive hip and knee OA. Of note, the presence of subchondral bone attrition in knee OA, defined as flattening or depression of the osseous articular surface, is strongly associated with subchondral bone marrow lesions (BMLs) onmagnetic resonance imaging. In turn, BMLs reflect the presence of active remodeling processes due to chronic overload.26 Cartilage loss occurs in the same knee subregions as subchondral bone attrition.27 In addition, it is possible that in posttraumatic OA, trabecular microarchitecture changes differ from those in primary OA. Indeed it has been proposed that during the early postoperative period in the canine ACL-deficient knee, disuse osteopenia can potentially occur due to decreased loadbearing.28 Likewise, subchondral bone in animal models of OA with early stages of the disease has shown both decreased volume and stiffness and increased remodeling.29 The impact of these subchondral bone changes in OA is still a matter for debate, in part due to the heterogeneity of the disease.


Table
Table. Etiopathogenic mechanisms and phenotypic features of atrophic osteoarthritis (OA), hypertrophic OA, and rheumatoid arthritis, and the involvement of osteoporosis.

Effects of systemic osteoporosis in osteoarthritis

A complex and paradoxical relationship seems to exist between OA and OP, although there is increasing evidence to support a close biomolecular and mechanical association between subchondral bone and cartilage.15 Indeed, microarray profiles have identified a number of genes differentially expressed in osteoarthritic bone that are key players in the structure and function of both bone and cartilage. These include genes involved in the Wingless-type mouse mammary tumor virus/β-catenin (Wnt/β-catenin) and transforming growth factor– β/mothers against decapentaplegic (TGF-β/SMAD) signaling pathways and their targets.30 Furthermore, aggrecan production, as well as SOX9, type II collagen, and parathyroid hormone–related protein mRNA expression, were inhibited in sclerotic but not nonsclerotic osteoblasts, while expression of MMP-3, MMP-13, and osteoblast-specific factor 1 by human OA chondrocytes was augmented in a coculture system. Thus, sclerotic osteoarthritic subchondral osteoblasts may contribute to cartilage degradation and chondrocyte hypertrophy.31 In addition, in our animal model of OA preceded by OP, improvement in subchondral bone integrity was shown to reduce the progression of cartilage damage, suggesting a direct relationship between these two conditions.32 On the other hand, several cross-sectional studies have demonstrated an inverse relationship between OP and OA,33,34 although others have produced opposite results.35 Confounding variables such as race, obesity, and physical activity could explain the mutually exclusive relationship between OA and OP, whereby overweight individuals and/or those who undertake excessive physical activity could have a higher risk of developing OA and having a higher bone mass.

Recently, we proposed that high as well as low bone mass conditions can result in OA induction and/or progression.5 Thus, both bone mass phenotypes may be considered risk factors for OA initiation. The presence of other risk factors such as skeletal shape abnormalities, joint overload, or obesity may have a synergistic effect regarding OA initiation. In addition, inflammatory mediators released by the articular cartilage in OA may lead to subchondral bone loss through increased bone remodeling. Accordingly, treatment goals for OA must consider improvement of subchondral bone integrity. This therapeutic approach should be individualized according to the patient’s bone mineral density status and OA phenotype, and the use of drugs should also subsequently be individualized for each patient. Recent findings suggest that the same drugs could be useful for treating both processes simultaneously, at least in a subgroup of patients with OA and concomitant OP.32

Effect of chronic synovitis on subchondral bone remodeling

Juxta-articular bone loss is related to the intensity of the inflammatory response in the affected joint.36,37 This fact is observed not only in rheumatoid arthritis, but also in other arthritides associated with a high degree of inflammation.38,39 Juvenile idiopathic arthritis, seronegative spondyloarthropathies, systemic lupus erythematosus, as well as septic arthritis, are all rheumatic diseases in which intense inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or the axial or appendicular skeleton.39

Various hormones, cytokines, and chemokines produced by the inflamed synovial membrane have been reported to be involved in juxta-articular osteoporosis in these diseases.36 The inflammatory mediators modulate the expression of the crucial factor RANKL, in whose presence macrophages differentiate into bone-resorbing osteoclasts in zones of contact between the inflamed synovium and subchondral bone, as described in rheumatoid arthritis.40 In addition to membrane bound RANKL in osteoblasts, RANKL secreted by synovial cells actively promotes bone destruction in chronic inflammatory arthritis.37 Hence, high local RANKL concentrations lead to increased osteoclastogenesis at the bone-pannus interface.

We have recently described that RANKL expressed by chondrocytes also contributes significantly to the pathogenesis of the juxta-articular bone loss associated with chronic arthritis in a rabbit model that develops a more intense and destructive version of the well-established antigen-induced arthritis (AIA).41 This experimental arthritis was found to be accompanied by severe juxta-articular bone loss, as estimated by x-ray and bone mineral density measurement. The increase in RANKL expression in the cartilage of AIA rabbits was linked to the particular presence of extracellular RANKL in the calcified cartilage. Previous results from our group have also shown that RANKL is localized in the extracellular matrix of human OA cartilage and could reach the subchondral bone through the calcified cartilage.42 These results indicate that chondrocyte-synthesized RANKL acts on subchondral bone cells, stimulating juxta-articular bone loss. Other studies have demonstrated that soluble RANKL produced by hypertrophic chondrocytes is a biologically active molecule during bone growth,43 acting in a paracrine manner on the subchondral bone plate. We have also shown that RANKL synthesized by prostaglandin E2–stimulated mature articular chondrocytes is also biologically active and is responsible for the mononuclear cell differentiation into osteoclast in the absence of exogenous RANKL.41

By contrast, in OA, mild synovial hyperplasia is predominantly present, with proliferation and activation of lining cells associated with fibrosis-related changes.44-46 Synovial inflammatory infiltrates are composed of mononuclear cells that appear in far less abundance than in the synoviumin rheumatoid arthritis, and they are distributed in a patchy pattern, mostly confined to areas adjacent to sites of damaged cartilage, thereby increasing OA severity throughout the disease course.47,48 The inflammatory synovial changes are associated with increased production of pro-inflammatory cytokines and mediators of OA joint damage.49 The Krenn synovitis score was found to be well correlated with subchondral bone structural parameters in an experimental model of OA preceded by OP.46 Furthermore, rabbits with surgery-induced knee OA showed a lower synovial inflammatory response and less subchondral bone loss than rabbits with AIA.41 Remarkably, RANKL expression in OA cartilage—particularly in calcified cartilage— was less than in AIA cartilage, suggesting that the relevant involvement of this osteoclastogenic molecule in subchondral bone loss in OA is smaller in degree than in chronic inflammatory arthritis.41

In addition, inflammation drives synovial angiogenesis through macrophage activation, which in turn perpetuates inflammation and synovial hyperplasia, inducing pannus formation to variable extents. This is a well-recognized pathogenic mechanism in the rheumatoid arthritis joint. Novel studies, however, have identified the presence of increased angiogenesis in the synovium, osteophytes, menisci, and osteochondral junction in OA patients.50 Channels extending from subchondral bone into non calcified articular cartilage provide the anatomical basis for angiogenesis and sensory nerve growth through the osteochondral junction. Thus, to different extents, angiogenesis also contributes to structural damage in chronic joint diseases.50

In summary, the intensity of the inflammatory response of the joint determines the juxta-articular bone loss in OA and chronic inflammatory arthritides. In articular conditions such as rheumatoid arthritis, the intense synovial and cartilage inflammation, pannus formation, and systemic bone loss will lead to high production of key biological mediators such as RANKL, which are involved in increased subchondral bone turnover with subsequent juxta-articular bone loss. By contrast, during the OA disease process, mild and patchy synovitis will occur with less RANKL expression in cartilage, resulting in lower subchondral bone turnover and subsequent bone loss than in rheumatoid arthritis–like conditions. In addition, angiogenesis and sensory nerve growth also contribute to joint damage to varying extents in these arthropathies. However, the main underlying pathogenic mechanisms may be common among these joint diseases. Further elucidation of the biological events involved in inflammation-induced bone loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss, and potentially joint damage progression, in these diseases. _


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Keywords: inflammatory arthritis; osteoarthritis; subchondral bone