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TWEAK and TNF Regulation of Sclerostin: A Novel Pathway for the Regulation of Bone Remodelling

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Advances in TNF Family Research

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 691))

Abstract

TNF-ligand and TNF-receptor family members have established essential roles in the regulation of bone remodelling. We showed recently that TWEAK is a novel mediator in a mouse model of inflammatory bone destruction and that osteoblast lineage cells expressed the TWEAK receptor, fibroblast growth factor-inducible gene 14 (Fn14). Subsequent studies have revealed that TWEAK has a number of effects on human primary osteoblasts, including the strong induction of cell proliferation and the inhibition of in vitro mineralisation. Most notably, TWEAK induced the expression of the negative regulator of bone mass, sclerostin. TWEAK and TNF-induced sclerostin expression synergistically and these effects were dependent on extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK) phosphorylation. While sclerostin expression was induced by TWEAK in proliferating cells, there was an inverse relationship between sclerostin expression and the proliferative potential in the responding cells. TWEAK and TNF were found to have divergent effects on other aspects of osteoblast behaviour, including the expression of a number of key genes involved in osteoblastogenesis and osteoblast function. These findings suggest that the roles of TWEAK and TNF need to be considered together in the regulation of physiologic as well as inflammation-driven osteoblast differentiation. In particular, the ways in which these cytokines may synergize or antagonize each other’s activity need to be elucidated further.

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Acknowledgments

The authors wish to acknowledge the contributions to this work by the co-authors of our recent publication [20]. We continue to be extremely grateful to the surgeons and nursing staff of the Department of Orthopaedics and Trauma, Royal Adelaide Hospital. This work was supported by the National Health and Medical Research Council of Australia (NHMRC). GJA was supported by a NHMRC R Douglas Wright Fellowship.

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Authors and Affiliations

  1. Bone Cell Biology Group, Discipline of Orthopaedics and Trauma, The University of Adelaide, Adelaide, 5000, SA, Australia

    David M. Findlay & Gerald J. Atkins

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  1. David M. Findlay
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  2. Gerald J. Atkins
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Correspondence to Gerald J. Atkins .

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Editors and Affiliations

  1. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    David Wallach

  2. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    Andrew Kovalenko

  3. Kennedy Institute of Rheumatology, Imperial College London, Aspenlea Rd. 1, London, W6 8LH, United Kingdom

    Marc Feldmann

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Findlay, D.M., Atkins, G.J. (2011). TWEAK and TNF Regulation of Sclerostin: A Novel Pathway for the Regulation of Bone Remodelling. In: Wallach, D., Kovalenko, A., Feldmann, M. (eds) Advances in TNF Family Research. Advances in Experimental Medicine and Biology, vol 691. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6612-4_34

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