Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway

Melissa M. Matzelle, Maxime A. Gallant, Keith W. Condon, Nicole C. Walsh, Catherine A. Manning, Gary S. Stein, Jane B. Lian, David Burr, Ellen M. Gravallese

Research output: Contribution to journalArticle

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Abstract

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. The aim of this study was to establish the mechanisms by which inflammation regulates osteoblast activity. Methods We characterized an innovative variant of a murine model of arthritis 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 ceased and appositional osteoblast-mediated bone formation was induced, resulting in repair of eroded bone. Resolution of inflammation was accompanied by striking changes in the expression of regulators of the Wnt/β-catenin pathway, which is critical for osteoblast differentiation and function. Down-regulation of the Wnt antagonists secreted frizzled-related protein 1 (sFRP1) and sFRP2 during the resolution phase paralleled 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.

Original languageEnglish
Pages (from-to)1540-1550
Number of pages11
JournalArthritis and Rheumatism
Volume64
Issue number5
DOIs
StatePublished - May 2012

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Wnt Signaling Pathway
Osteoblasts
Inflammation
Bone and Bones
Osteogenesis
Joints
Arthritis
Rheumatoid Arthritis
Osteitis
Catenins
Osteoclasts
Bone Resorption
Inbred C57BL Mouse
Down-Regulation
Serum

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Matzelle, M. M., Gallant, M. A., Condon, K. W., Walsh, N. C., Manning, C. A., Stein, G. S., ... Gravallese, E. M. (2012). Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis and Rheumatism, 64(5), 1540-1550. https://doi.org/10.1002/art.33504

Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. / Matzelle, Melissa M.; Gallant, Maxime A.; Condon, Keith W.; Walsh, Nicole C.; Manning, Catherine A.; Stein, Gary S.; Lian, Jane B.; Burr, David; Gravallese, Ellen M.

In: Arthritis and Rheumatism, Vol. 64, No. 5, 05.2012, p. 1540-1550.

Research output: Contribution to journalArticle

Matzelle, MM, Gallant, MA, Condon, KW, Walsh, NC, Manning, CA, Stein, GS, Lian, JB, Burr, D & Gravallese, EM 2012, 'Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway', Arthritis and Rheumatism, vol. 64, no. 5, pp. 1540-1550. https://doi.org/10.1002/art.33504
Matzelle MM, Gallant MA, Condon KW, Walsh NC, Manning CA, Stein GS et al. Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis and Rheumatism. 2012 May;64(5):1540-1550. https://doi.org/10.1002/art.33504
Matzelle, Melissa M. ; Gallant, Maxime A. ; Condon, Keith W. ; Walsh, Nicole C. ; Manning, Catherine A. ; Stein, Gary S. ; Lian, Jane B. ; Burr, David ; Gravallese, Ellen M. / Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 5. pp. 1540-1550.
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abstract = "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. The aim of this study was to establish the mechanisms by which inflammation regulates osteoblast activity. Methods We characterized an innovative variant of a murine model of arthritis 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 ceased and appositional osteoblast-mediated bone formation was induced, resulting in repair of eroded bone. Resolution of inflammation was accompanied by striking changes in the expression of regulators of the Wnt/β-catenin pathway, which is critical for osteoblast differentiation and function. Down-regulation of the Wnt antagonists secreted frizzled-related protein 1 (sFRP1) and sFRP2 during the resolution phase paralleled 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.",
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N2 - 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. The aim of this study was to establish the mechanisms by which inflammation regulates osteoblast activity. Methods We characterized an innovative variant of a murine model of arthritis 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 ceased and appositional osteoblast-mediated bone formation was induced, resulting in repair of eroded bone. Resolution of inflammation was accompanied by striking changes in the expression of regulators of the Wnt/β-catenin pathway, which is critical for osteoblast differentiation and function. Down-regulation of the Wnt antagonists secreted frizzled-related protein 1 (sFRP1) and sFRP2 during the resolution phase paralleled 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.

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