Inflammation in arthritis induces expression of BMP3, an inhibitor of bone formation

Abstract

Objectives: Inflammation in diseases such as rheumatoid arthritis (RA) stimulates osteoclast-mediated articular bone erosion and inhibits osteoblast-mediated bone formation, leading to a net loss of bone. Pro-inflammatory cytokines and antagonists of the Wnt signalling pathway have been implicated in the inhibition of osteoblast differentiation and activity in RA, contributing to the erosive process and impairing erosion healing. Importantly, osteoblast differentiation and function are also regulated by the osteogenic bone morphogenetic protein (BMP) signalling pathway, which is antagonized by BMP3. We therefore examined the potential role of BMP3 in inflammatory arthritis.

Method: Two murine models of RA, K/BxN serum transfer arthritis (STA) and antigen-induced arthritis (AIA), were used to establish the temporal expression of BMP3 and the cellular sources of BMP3 mRNA and protein in inflammatory arthritis. To determine the effects of inflammation on the expression of BMP3 in osteoblasts, murine calvarial osteoblasts were treated with pro-inflammatory cytokines and BMP3 expression was assessed.

Results: In both murine models of RA, BMP3 mRNA and protein are highly expressed by osteoblasts lining inflammation–bone interfaces late in the course of arthritis. Synovial tissues are not a significant source of BMP3. BMP3 expression is induced in osteocalcin-expressing osteoblasts in vitro following stimulation by tumour necrosis factor (TNF).

Conclusions: These data implicate BMP3 as a novel factor that may act locally to contribute to the erosive process and inhibit the repair of articular bone in RA through inhibition of osteoblast differentiation and function.

Acknowledgements

We thank Teresa Bowman for technical assistance, and Kara Lindquist and Jonathan Lowery for preliminary studies.

Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number NIH 1RO1-AR055952 (EMG), the Abbott Bioresearch Fellowship in Translational Science (MMM), and a grant from the Arthritis National Research Foundation (SK).