An earlier concept that targeted repair of the subchondral bone is initiated in response to the formation of microfractures was revived when it was observed that the elastic modulus (stiffness) of the tissue was reduced locally due to an increase in vascularization and in the remodeling rate . These changes would lead to reactivation of the secondary ossification center and a decrease in cartilage thickness . The concept that modified remodeling or bone turnover causes cartilage degradation, as opposed to an effect of subchondral bone plate thickening, is also supported by animal studies that showed the severity of OA lesions was greater and progression of the disease more rapid in guinea pigs, animals that had the highest bone turnover rate, notwithstanding an initial difference in the thickness of the subchondralbone . This suggests that bone tissue homeostasis and turnover are more important for the appearance and progression of Oa than the state of the bone tissue at a given time point. It is the mechanical disturbance of the joint tissues that would then induce local responses that lead to the thinning of the articular cartilage. This in turn would contribute to shear stress and lead to complete cartilage loss.
There is still speculation as to whether the abnormal structure and metabolism of subchondral bone are linked to the development/progression of cartilage damage. Some studies have indicated that subchondral bone changes precede and may be responsible for the evolution of cartilage lesions [35,89,193]. Other studies have indicated that subchon-dral bone changes proceed simultaneously or even follow changes in cartilage. Subchon-dral bone changes, therefore, would be only secondary to cartilage degradation [20,29,38]. Although the pathways involved in crosstalk between subchondral bone and cartilage remain largely unknown, several factors synthesized by subchondral bone cells are capable of inducing metabolic changes in the cartilage.
Subchondral bone tissue may, by the production of cytokines and growth factors, induce OA [29,32,112]. Bone does produce a number of proinflammatory cytokines and growth factors that are involved in tissue remodeling and modulate cartilage catabolism. Early pathologic studies have shown that clefts or channels in the tidemark appear early in OA [31,160,166, 223,234]. This indicates a possible way to traffic cytokines and growth factors from the subchon-dral compartment to the overlying cartilage. Fatigue microcracks are also observed in articular cartilage  and may serve as channels for signal molecules from bone to cartilage. This does not rule out the possibility that these molecules diffuse within the bone extracellular matrix to reach the articular cartilage. Indeed, because healthy cartilage is considered avas-cular and aneural, nutrients must enter articular cartilage either from the surface, via the synovial fluid, or from the underlying subchon-dral bone.
For a long period of time, synovial fluid was believed to be the only nutrient route, because of the absence of an anatomic barrier and because the cartilage cannot survive when not nourished by the synovial fluid . However, in a number of circumstances, cartilage degenerates even when still in contact with normal synovial fluid. Nutrient supply of articular cartilage by subchondral bone may seem obvious, but the dense calcification in the basal zone of normal articular cartilage has been considered an insurmountable barrier to solute and fluid diffusion [61,112]. However, Malinin and Ouellette  have demonstrated that when baboon cartilage is deprived of contact with subchondral bone for any length of time, degenerates as in OA. Therefore, both routes of nutrient entry may coexist. Hence, bone-derived products may indeed drive cartilage metabolism [158,241]. Potential candidates are IGF-1, TGF-|, and interleukin-1| and -6 (IL-1|, IL-6). The IGFs are important growth factors that regulate bone formation . Osteoarthritic subchondral osteoblasts produce variable total IGF-1 levels and less IGF binding proteins compared to normal [101,148,150]. This results in higher levels of free IGF-1 that seem to promote bone remodeling [101,147] and increase bone stiffness, a situation that exacerbates cartilage matrix degradation . Both TGF-| and IGF-1 are involved in matrix deposition and turnover, with TGF-| stimulating matrix synthesis  and collagenase activity, whereas IGF-1 inhibits matrix development in bone cells . The increase in growth factors is likely to favor matrix deposition in bone and to limit overall degradation. In this connection it is worth calling attention to a study in murine knee joints that showed that intraarticular injections of TGF-| into the joint induce osteoarthritic-like changes . Blocking endogenous TGF-| production during experimental osteoarthritis prevents osteophyte formation . The localized effect of TGF-| and IGF-1 maybe linked to an abnormal response to leptin by OA subchon-dral osteoblasts. This may be so because the expression of leptin stimulates TGF-| and IGF-1 in joints .
Of the cytokines and eicosanoids produced by bone cells, IL-1|, IL-6, PGE2, and LTB4 are the major molecules that modulate turnover of the extracellular matrix. Osteoarthritis patients can be characterized as low and high producers of PGE2 and IL-6 on the basis of the culture of their subchondral osteoblasts . PGE2 production is inversely correlated with the synthesis of LTB4 . This is the opposite of what is found in normal subchon-dral bone [149,176] and may contribute to promoting new matrix deposition and bone formation in OA [73,116]. However, the new matrix is undermineralized. At low concentrations, PGE2 stimulates bone formation, but appears inhibitory at high concentrations [93,111,194]. PGE2 stimulates collagen synthesis and promotes osteoblast proliferation. In contrast, leukotrienes stimulate osteo-clast differentiation and bone resorption .
Therefore, when the ratio of PGE2/LTB4 is high in OA, osteoblasts may promote subchon-dral bone formation. On the other hand, IL-1P and IL-6 promote matrix degradation in both bone and cartilage by their action on specific MMPs . Conceivably these actions are related to the fact that the disease progresses slowly in some patients, but rapidly in others . Because Oa patients can be classified by their LTB4 levels, and because LTs are more potent inflammatory mediators than PGE2 [84,139,181], this may explain the protective role of n-3 polyunsaturated fatty acids (PUFAs) in OA chondrocytes , particularly because PUFAs modulate the inflammatory process [1,133,184,238].
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