It is well known that OA differs in men and women. Men younger than 50 tend to be most affected by OA, whereas, in people over 50, two thirds of the OA patients tend to be women . The reason for this is unclear. Osteoarthritis in younger men is considered to be an occupational disease. In contrast, the high incidence in postmenopausal women suggests that the change in hormonal status may play a role in the OA process. However studies dealing with the protective effect of estrogens show conflicting results (reviewed in [67,95,203]). A study in cynomolgus monkeys has shown that long-term estrogen replacement therapy significantly reduces the severity of OA lesions . These data conflict with a common notion that, as noted for many years, there is an inverse relationship between OA and osteoporosis . However, considering the prevalence and characteristics of the two diseases, it would not be surprising if they coexisted on occasion . Moreover, some patients present with nonprogressive OA, whereas others with progressive OA also have increased bone resorption . Conceivably the latter category of patients respond to estrogen therapy. Interestingly, a recent study suggests that antagonists of cannabinnoid receptors can protect against bone resorption . Magnetic resonance imaging can help obtain a more precise estimate of the effects of estrogens on cartilage and bone. Estrogens may prevent some metabolic changes in subchondral bone osteoblasts and in chondrocytes, thereby causing a slowdown in the onset of OA. The efficacy of estrogen therapy may also be due to genetic susceptibility. Indeed, the estrogen a-receptor gene (ESR1) has been identified as a candidate gene that may be involved in OA (reviewed in [137,177]).
Genetic studies have pointed to a recessively inherited gene. Because the cause of OA is likely multifactorial, the "gene" more probably expresses a factor involved in a metabolic pathway rather than a structural protein. Some studies examining a metabolic link between obesity and OA have reported a significant association between hypertension, uric acid, cholesterol, and OA, whereas others failed to substantiate these relationships [48,146,220,225]. A unifying hypothesis could be that OA is a metabolic disease in which systemic or local factors induce changes in skeletal tissues. As tissue homeostasis is disturbed and joint integrity impaired, normal wear and tear could lead to cartilage damage, the hallmark of OA. The loss of cartilage may then be the result of mechanical forces, but this would not be the cause of the disease itself. Furthermore, the OA process may modify the formation and biosynthetic activity of cells derived from mesenchymal stem cells (MSCs) . Osteoblasts derived from mesenchymal precursor cells can also give rise to chondrocytes, myoblasts, adipocytes, and tendon cells , all cells affected by OA. However, when bone marrow MSCs from OA patients were cultured, they did not exhibit altered in vitro proliferation, nor did the number of osteogenic precursors change with age . This contrasts with observations on osteoporotic patients. Nonetheless, the osteogenic activity of MSCs of patients with advanced OA is enhanced, whereas their chondrogenic and adipogenic activity is reduced . Because adipocytes share a common mesenchymal stem cell precursor with osteoblasts, chondrocytes, tenocytes, and myoblasts, a link may exist between lipid and connective tissue metabolism in OA . The link may be leptin, a systemic factor that plays a role in body weight regulation, lipid metabolism, and obesity. Indeed leptin may be a key factor in the etiology of OA [60,124,138].
The potential role of bone tissue in OA initiation or progression may also be due to its capacity to serve as a reservoir for MSCs and to provide nutrition for the hyaline cartilage. The role of mesenchymal cells in the appearance or progression of OA is a key issue that has received recent attention. Because there is increasing evidence of the abnormal behavior and phenotypic features of osteoblasts, chondrocytes, myoblasts, and tenocytes in OA joints, MSC development and differentiation are likely to be altered in affected individuals. Evidence indicates that MSC numbers, proliferation rate, population-doubling time and the capacity to differentiate into different lineage cells may be altered in OA [58,168,169]. The response to cytokines and growth factors by MSCs in OA individuals may also be altered . This may indicate that their differentiation into target cells is also altered in vivo, leading to abnormal tissue homeostasis [140,211]. It also suggests that cells not presently residing in the affected tissue may profoundly affect behavior and homeostasis of this tissue. The number of MSCs characterized by in vitro multilineage potential is larger in OA than in rheumatoid arthritis synovial fluid . This indicates that, although related, these two diseases have diverging etiology and progression. Moreover, because the chondrogenic and adipogenic capacity of OA MSCs is impaired , OA MSCs either remain undifferentiated or differentiate into limited lineage cells, such as the osteogenic line. This can explain why all joint tissues except bone are impaired or reduced in OA individuals. Indeed, although muscle strength is reduced beyond the normal age-related loss , possibly due to muscle cell dysfunction , alterations in the differentiation capacity of MSCs to form myocytes may also be altered in these individuals.
Even more importantly, this alteration in MSCs may also affect the important immunore-gulatory role played by MSCs in OA tissues [55,119,121]. This regulatory role is modulated by the action of specific signaling molecules such as TGF-P and HGF. In this connection it is important to remember the key role played by cytokines and growth factors in osteophyte formation, and the elevation of TGF-P  and HGF levels in OA cartilage, although the role of HGF is uncertain. Osteophyte formation maybe considered a repair response to stabilize the damaged joints. It requires the local recruitment of specific MSCs. This demonstrates the potential therapeutic role stem cells may play in OA joints.
Recent genome-wide scans have revealed an OA susceptibility locus on chromosome 11q, in close proximity to the low-density lipoprotein receptor-related protein 5 (LRP5). This gene product controls bone mass and may be the cause of the abnormal bone tissue mineralization and remodeling observed in OA patients. Although no individual polymorphisms were found in a study of 187 individuals, an altered haplotype of LRP5 was identified that increases the risk of OA 1.6 fold . Therefore, LRP5 and the associated Wnt signaling pathway may constitute significant factors in the pathology of OA.
Felson et al.  have provided an interesting new perspective on subchondral bone marrow changes in OA. They found a strong correlation between the marrow edema and pain, but not with the severity of pain. In a longitudinal study, they also found that bone marrow edema was largely related to limb alignment [214,219]. Medial bone marrow lesions were seen mainly in patients with varus limbs, and lateral lesions were seen mostly in patients with valgus limbs. However, even after adjustment for misalignment, bone marrow edema lesions were still strongly associated with radiographic progression.
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