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Lories, R.J. et al.

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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