New emerging roles of transcription factor Pitx1 and Reg growth factors in osteoarthritis pathogenesis

The key features of osteoarthritis (OA) are the focal destruction of the articular cartilage and the abnormal growth of the subchondral bone producing outgrowths. Since in humans OA develops and changes very slowly, it is difficult to follow that disease over any length of time. Besides that, the heterogeneity of the disease results in controversy as regards its aetiology and progression. Thus, study of early events of the degenerative process cannot be made in humans and recourse must be made to animal models. We have recently inactivated the transcription factor Pitx1, which is highly expressed in articular and growth plate chondrocytes during mouse development. Pitx1-null mice displayed poorly developed joints, which are markedly apoptotic. Interestingly, Pitx1 mice that are phenotypically normal at birth exhibit with aging clinical features of OA such as progressive joint stiffness associated with an abnormal fibrillation and calcification of their articular cartilage. Histological analysis of mineralized adult femurs and tibias revealed also an increased thickening of subchondral, trabecular and cortical bone. At the molecular level, expression analysis of Pitx1-null and Pitx1 mice allowed one to identify and characterize a novel molecular cascade involved in OA pathogenesis. To assess whether a loss-of-function of Pitx1 transcription factor in human articular chondrocytes and the subsequent activation of Reg growth factors trigger OA pathogenesis. RNA isolated from articular cartilage of Pitx1-null mice and from patients with OA and age-matched and gender-matched subjects were prepared to perform a molecular expression analysis. In parallel, cartilage explants were analyzed by immunohistochemistry method to detect the presence of Reg I proteins, and transient transfection assays were performed to assess the contribution of Reg growth factors in the activation of NF-κB induced by proinflammatory cytokines in OA. Expression analysis showed the expression of Pitx1 only in matched controls. Moreover, the lack of Pitx1 in OA articular chondrocytes leads to a marked up regulation of Reg I growth factor and its receptor, which has been confirmed at the protein level by immunohistochemistry assays with human Reg I antibodies on OA articular cartilage. We have also demonstrated in vitro that the gain-of-function of Reg receptor enhances by several fold the activation of NF-κB induced by tumor necrosis factor alpha or IL-1β, suggesting that Reg signaling activity is a key mediator of proinflammatory cytokine action in OA pathogenesis. This was further supported by the fact that gain-of-function of Pitx1 abrogates Reg I, Reg II and Reg receptor expression completely, which may explain why proinflammatory cytokines cannot activate NF-κB in cells devoid of Reg receptor. Taken together these results revealed the role of new emerging transcription and growth factors involved in OA pathogenesis, which could lead to a more rational approach for the development of better therapeutic compounds to prevent and cure OA.

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