The role of changes in the subchondral bone in the pathogenesis of osteoarthritis

Along with the degeneration of articular cartilage, the pathological process in osteoarthritis involves the underlying bone tissue. It is suggested that the thickening of the subchondral plate promotes the progression of osteoarthritis. As osteoarthritis progresses, articular cartilage, which is an object for mechanical and chemical stress, is slowly eroded due to an imbalance in the processes of catabolism and cartilage repair. In particular, mechanical stress in relation to the "weight-bearing" body mass of the joints contributes to the formation of a large number of micro-fractures in the subchondral plate and cartilage. As the articular cartilage erodes, sclerosis of the subchondral bone progresses, the stiffness of the bone tissue increases, which in turn contributes to a further disruption of the articular cartilage structure. However, the question of the primary or secondary nature of changes in the subchondral bone in osteoarthrosis remains unresolved.

Until recently, it was believed that the radiographically determined changes in the spongy substance of the subchondral bone, such as sclerosis or cyst formation, in patients with osteoarthritis are secondary. However, the results of clinical and experimental studies indicate a possible initiating role of subchondral bone in the pathogenesis of osteoarthritis. One possible mechanism is a sharp increase in the stiffness gradient of the subchondral bone due to the fact that the integrity of the proper cartilaginous tissue depends on the mechanical properties of its bone "bed". Studies in primates have shown that changes in the subchondral bone may precede changes in articular cartilage. The evidence in the models of osteoarthrosis in animals and clinical studies of evidence in support of this hypothesis and against it only exacerbated the discussion. Thickening of trabeculae in the subchondral bone is not always accompanied by an increase in mineralization of bone tissue, or rather, an increase in the volume of the osteoid. This sign of abnormal mineralization indicates that a disturbance in the regulation of bone remodeling is an integral part of osteoarthrosis, and also supports the concept of bone tissue defect in osteoarthritis. The J. Dequeker group (1989) views the latter as a "generalized metabolic bone disease".

Bone tissue is constantly updated. This dynamic process, called bone remodeling, is a complex sequence of processes of resorption and mineralization. Osteoclasts resorb bone tissue, and osteoblasts secrete proteins that form the main organic component for mineralization. The formation and resorption of bone does not happen randomly throughout the skeleton, it is a programmed process occurring in various parts of the skeleton, called bone remodeling units. At the beginning of the cycle, osteoclasts appear on the inactive surface; Within 2 weeks they form a tunnel in the cortical bone layer or lacuna on the surface of the trabecular bone. The frequency of activation of new bone remodeling units determines the degree of bone tissue renewal. In a healthy young person the processes of formation and resorption of bone tissue are balanced, the normal mass of bone tissue is maintained. In the hormonal regulation of bone resorption, at least PTH and PGE ₂, not only osteoclasts but also osteoblasts take part, since under the action of these hormones, factors stimulating bone resorption by osteoclasts are released. Currently, there are more than 12 local and systemic bone growth regulators that affect its remodeling, in particular PTH, 1,25 (OH) ₂ D ₃, calcitonin, growth hormone, glucocorticoids, thyroid hormones, insulin, IGF (1 and 2), estrogens, PGE ₂, androgens.

Bone cells release a number of proteins and cytokines, which carry out endocrine regulation and signal transmission. Proteins produced by osteoblasts include bone matrix proteins such as collagen, osteopontin, osteocalcin, bone sialoproteins. In addition, these cells release proteases both in active and latent form, which participate in the process of bone remodeling - MMP, components of the plasminogen activator (AP) / plasmin activator system. The cytokines released by osteoblasts can act both through autocrine mechanisms and paracrine to local cells (other osteoblasts, osteoclasts).

It is not yet known which way these signals are regulated - by mechanical stress or other chemical signals induced by mechanical stress. However, it is known that repeated mechanical stress causes local proliferation of bone cells and / or proteins. In vivo, mechanical stress can activate osteoblasts, increase cyclic nucleotide levels, produce prostaglandins, and also cause morphological changes associated with bone remodeling. In vitro, mechanical stress causes the proliferation of osteoblast culture, the expression of mRNA of bone proteins involved in osteoid formation and during mineralization, the release of local growth factors such as IGF-1 and IGF-2 and adhesion molecules. The transmission of a signal of mechanical stress can be accomplished through mechanically sensitive ion channels.

There are indirect evidence of impaired osteoblast function in osteoarthritis. G. Gevers and J. Dequeker (1987) demonstrated an increase in serum osteocalcin levels in women with osteoarthritis of the joints of the hands, as well as in explants of the cortical bone zone, which indicates that the pathology of the bone tissue can be part of osteoarthrosis. In autopsy, not only the thickening of the subchondral bone was detected, but also the abnormally low mineralization of the femoral head. In guinea pigs with surgically induced osteoarthritis, a significant thickening of the bone fraction in the subchondral zone was detected using computed tomography. The imbalance between collagen and non-collagen (osteocalcin and other) proteins can lead to an increase in the volume of bone tissue, but does not affect its mineral density. According to M. Shimizu and co-authors (1993), the progression of degenerative changes in articular cartilage is associated with a more intensive remodeling of the subchondral bone and an increase in its stiffness, which also indicates a defect in bone cells in osteoarthritis. According to the hypothesis suggested by V. Lee and M. Aspden (1997), the proliferation of defective bone cells can lead to an increase in bone stiffness, but does not cause an increase in its mineral density.

CI Westacott and co-authors (1997) hypothesized that abnormal osteoblasts directly affect the metabolism of cartilaginous tissue. Cultivating osteoblasts of patients with osteoarthrosis with chondrocytes of people who did not have joint diseases, the authors observed a significant change in the release of glycosaminoglycans by normal cartilage tissue in vitro, but the level of cytokine release remained unchanged. G. Hilal and co-authors (1998) have shown that the culture of osteoblasts of the subchondral bone of patients with osteoarthritis in vitro has an altered metabolism - the activity of the AP / plasmin system and the level of IGF-1 in these cells are increased. The observation of CI Westacott et al. (1997) can be explained by an increase in protease activity in subchondral bone cells.

It remains unknown whether osteoarthrosis initiates changes in the subchondral bone or contributes to its progression. DK Dedrick and co-authors (1993) demonstrated that in dogs with surgically induced osteoarthritis, thickening of the subchondral bone is not a prerequisite for the development of osteoarthrosis changes in articular cartilage, but it contributes to the progression of degenerative processes in the cartilage. The results of the study of A. Sa'ied and co-authors (1997) contradict the data of the previous study. Using 50 MHz echography to evaluate initial morphological changes and their progression in articular cartilage and bone in experimental osteoarthritis induced by injecting monoiodoacetic acid into the rat knee, the authors demonstrated a simultaneous process of changes in bone and cartilage within the first three days after injection.

Osteoblasts secrete growth factors and cytokines that participate in local remodeling of bone tissue, which can contribute to remodeling the proper cartilaginous tissue in the "weight-bearing" joints after they penetrate the microcracks in the calcified layer of articular cartilage. Moreover, the products of bone cell secretion are found in the synovial fluid. The most likely products released by abnormal osteoblasts capable of triggering the local remodeling of cartilaginous tissue are TGF-b and bone morphometric proteins (CML). Both representatives of the TGF family are distinguished by chondrocytes and osteoblasts, and both are able to modify the remodeling of both bone and cartilaginous tissue. J. Martel Pelletier et al. (1997) observed an increase in the level of TGF-P in explants of the subchondral bone of patients with osteoarthritis in comparison with healthy people, which indicates the probable role of this growth factor in the pathogenesis of osteoarthrosis. IGF is also produced by osteoblasts. In the culture of osteoblast-like cells obtained from patients with osteoarthritis, an increase in the level of IGF that alter the metabolism of cartilage has been found.

TGF-b, IGF, CML, and cytokines produced by osteoblasts in the subchondral bone can affect the production of collagenase and other proteolytic enzymes in the cartilage, which in turn can contribute to the remodeling / degradation of the cartilage matrix. It remains unclear whether osteoblasts develop with OA less macrophage colony-stimulating factor (M-CSF - bone resorption stimulator) than normal cells. The results of AG Uitterlinden et al. (1997) have shown that a role in the formation of osteophytes can be played by vitamin D receptors that are expressed by osteoblasts and regulate the expression of a number of factors synthesized by these cells, which in part explains the role of osteoblasts in the pathogenesis of this disease.

Taking into account the results of the above studies, G. Hilal et al. (1998), J. Martel-Pelletier et al. (1997) proposed the following working hypothesis for the relationship between the remodeling of the subchondral bone and the proper articular cartilage in osteoarthritis. At an early or extended stage of OA pathogenesis, the process of bone tissue remodeling in the subchondral bone is intensified. Simultaneously, repeated loading leads to local micro-fractures and / or the appearance of an imbalance of the IGF-IGF-binding protein (IHFB) system due to an abnormal response of the subchondral bone osteoblast, which contributes to its sclerosis. The latter in turn can contribute to the appearance of micro-fractures of the proper cartilage and damage to its matrix.

Under normal conditions this damage is eliminated by local synthesis and release of IGF-1 and IGF-binding protein, which stimulate the formation of ECM of articular cartilage. At the same time, the PD system promotes the growth of subchondral bone cells and the formation of bone matrix. Anabolic activity of the IGF-system is increased in the subchondral bone of patients with osteoarthritis, whereas local activation of the AP / plasmin system (local regulator of the IGF system) in the articular cartilage causes its local changes. In osteoblasts with osteoarthrosis, IGF-1 disrupts the regulation of AP by plasmin in the form of positive feedback, therefore, it can restrain remodeling in the bone tissue, which ultimately leads to subchondral sclerosis. Thus, in the bone and cartilage tissue, the local induction of IGF-1 and protease leads, on the one hand, to cartilage damage, on the other hand to the thickening of the subchondral bone, the latter in turn contributing to further damage to the cartilage. The imbalance between cartilage damage associated with subchondral sclerosis and its reparative abilities leads to a progressive change in cartilage VKM and to the development of osteoarthritis. According to the authors, this hypothesis also explains the slow progression of the disease.