Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway
Department of Cell Biology; Department of Medicine, Division of Rheumatology
Wnt Signaling Pathway; Inflammation; Osteoblasts; Bone Resorption
Cell Biology | Rheumatology
OBJECTIVE: Inflammation in the bone microenvironment stimulates osteoclast differentiation, resulting in uncoupling of resorption and formation. Mechanisms contributing to the inhibition of osteoblast function in inflammatory diseases, however, have not been elucidated. Rheumatoid arthritis (RA) is a prototype of an inflammatory arthritis that results in focal loss of articular bone. The paucity of bone repair in inflammatory diseases such as RA raises compelling questions regarding the impact of inflammation on bone formation.
METHODS: To establish the mechanisms by which inflammation regulates osteoblast activity, we characterized an innovative variant of a murine arthritis model in which inflammation is induced in C57BL/6J mice by transfer of arthritogenic K/BxN serum and allowed to resolve.
RESULTS: In the setting of resolving inflammation, bone resorption ceases and appositional, osteoblast-mediated bone formation is induced, resulting in repair of eroded bone. Resolution of inflammation is accompanied by striking changes in expression of regulators of the Wnt/beta-catenin pathway, a pathway critical for osteoblast differentiation and function. Downregulation of the Wnt antagonists sFRP1 and sFRP2 during the resolution phase parallels induction of the anabolic and pro-matrix mineralization factors Wnt10b and DKK2, demonstrating the role of inflammation in regulating Wnt signaling.
CONCLUSION: Repair of articular bone erosion occurs in the setting of resolving inflammation, accompanied by alterations in the Wnt signaling pathway. These data imply that in inflammatory diseases that result in persistent articular bone loss, strict control of inflammation may not be achieved, and may be essential for the generation of an anabolic microenvironment that supports bone formation and repair.
DOI of Published Version
Arthritis Rheum. 2011 Dec 2. doi: 10.1002/art.33504. Link to article on publisher's site
Arthritis and rheumatism
Matzelle, Melissa M.; Gallant, Maxime A.; Condon, Keith W.; Walsh, Nicole; Manning, Catherine A.; Stein, Gary S.; Lian, Jane B.; Burr, David B.; and Gravallese, Ellen M., "Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway" (2011). Stein, Stein, Lian, vanWijnen Lab Publications. 246.