TGF-β induces Wnt10b in osteoclasts from female mice to enhance coupling to osteoblasts

Kuniaki Ota, Patrick Quint, Ming Ruan, Larry Pederson, Jennifer J. Westendorf, Sundeep Khosla, Merry Jo Oursler

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

In young adults, bone lost through osteoclast-mediated resorption is precisely replaced in both location and amount. Understanding how these two processes are coupled is crucial to advancing treatments for osteoporosis, a disease that progresses when the processes become uncoupled. We documented that osteoclasts secrete the mammalian integration 1 gene that is the homolog of Drosophila Wngless (Wnt) 10b, bone morphogenetic protein 6 (BMP6), and the chemokine sphingosin 1 phosphate (S1P) to promote mesenchymal cell mineralization in vitro. During bone resorption, TGF-β1 is released from the bone extracellular matrix and activated by osteoclasts. Thus, TGF-β1 levels are elevated during the resorption phase of bone turnover. We therefore investigated the influences of TGF-β1 on osteoclast-mediated support of mineralization. TGF-β1 increased osteoclast production of Wnt10b, but not BMP6 or S1P. Blocking Wnt10b activity with the Wnt signaling inhibitor Dickkoph-related protein 1 suppressed the ability of TGF-β-treated osteoclast-conditioned media to promote osteoblast mineralization. Examination of TGF-β signaling in osteoclasts revealed that induction of Wnt10b expression was dependent on Smad2/3 activation and independent from TGF-β1 stimulation of protein kinase B (AKT) or MAPK kinase. TGF-β1-treated osteoclast-conditioned media from cells with blocked Smad signaling exhibited a reduced ability to support mineralization, demonstrating the importance of Smad signaling in this response. Parallel cultures with suppressed TGF-β activation of AKT or MAPK kinase signaling retained their ability to elevate mineralization. These results demonstrate that TGF-β1 stimulates Wnt10b production in osteoclasts, which may enhance restoration of the bone lost during the resorptive phase of bone turnover.

Original languageEnglish
Pages (from-to)3745-3752
Number of pages8
JournalEndocrinology
Volume154
Issue number10
DOIs
Publication statusPublished - 2013 Oct 1

ASJC Scopus subject areas

  • Endocrinology

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    Ota, K., Quint, P., Ruan, M., Pederson, L., Westendorf, J. J., Khosla, S., & Oursler, M. J. (2013). TGF-β induces Wnt10b in osteoclasts from female mice to enhance coupling to osteoblasts. Endocrinology, 154(10), 3745-3752. https://doi.org/10.1210/en.2013-1272