Noggin haploinsufficiency differentially affects tissue responses in destructive and remodeling arthritis.
OBJECTIVE: The balance between destruction and homeostatic or reparative responses determines the outcome of arthritis. Increasing evidence suggests a role for signaling pathways, essential for development and growth, in the maintenance of tissue homeostasis and attempts at repair. Inappropriate activation of such pathways may also have a role in disease progression. We undertook this study to determine the effect of shifting the balance in bone morphogenetic protein ( BMP) signaling in different mouse models of arthritis. METHODS: Endogenous levels of noggin, a BMP antagonist, were reduced using heterozygous noggin(+/LacZ) mice in a model of inflammation-driven destruction (methylated bovine serum albumin [mBSA]-induced monarthritis), a model of systemic autoimmune arthritis (collagen-induced arthritis [CIA]), and a model of joint ankylosis (spontaneous arthritis in DBA/1 mice). In addition, we studied BMP inactivation by adenoviral noggin overexpression in destructive arthritis. Cartilage damage and activation of BMP signaling were studied by digital image analysis using Safranin O sulfated glycosaminoglycan staining and immunohistochemistry for phosphorylated Smads (Smads 1, 5, and 8), respectively. RESULTS: Noggin haploinsufficiency provided protection for articular cartilage against destruction in mBSA-induced arthritis. Antagonist overexpression rendered cartilage more vulnerable in this model. Noggin gene transfer in knees affected by CIA also enhanced cartilage damage. Haploinsufficiency did not affect CIA, but noggin(+/LacZ) mice had an increased number of CD4-positive cells with normal immune responses. In noggin(+/LacZ) DBA/1 mice with spontaneous arthritis, we observed delayed progression from cartilage to bone formation. CONCLUSION: Tight spatiotemporal control of BMP signaling appears to be critical in the response of joint tissues in models of arthritis.[1]References
- Noggin haploinsufficiency differentially affects tissue responses in destructive and remodeling arthritis. Lories, R.J., Daans, M., Derese, I., Matthys, P., Kasran, A., Tylzanowski, P., Ceuppens, J.L., Luyten, F.P. Arthritis Rheum. (2006) [Pubmed]
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