TGF-β Induces Wnt10b in Osteoclasts From Female Mice to Enhance Coupling to Osteoblasts

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.

Sphingosine 1-Phosphate in Blood: Function, Metabolism, and Fate

“…Others found that S1P production via SphK1 in osteoclasts and its secretion stimulates osteoblast migration and survival, which supports bone formation [79,80,81,82]. In a different study, the role of TGF-beta1 on osteoclast-mediated support of mineralization was investigated and revealed that S1P production was, however, not induced in osteoclasts upon TGF-beta1 stimulation [83]. Up-regulation of OPG and osteoblast differentiation markers upon S1P stimulation was another finding which may lead to the inhibition of osteoclast differentiation and promotion of bone formation [84].…”

Osteoclasts—Key Players in Skeletal Health and Disease

“…TGF-β and IGF-1 are both stored in bone matrix and released by its resorption by OC, with the former acting to promote migration of mesenchymal stem cells to newly resorbed sites (136, 137). TGF-β also induces OC to express CXCL16 and Wnt10b, which induce recruitment and mineralization by osteoblasts, respectively (138, 139). Sphingosine-1-phosphate (140) and collagen triple helix repeat containing 1 (141) have been proposed as possible secreted coupling factors that enhance bone formation.…”

Prostaglandin-mediated inhibition of PTH-stimulated β-catenin signaling in osteoblasts by bone marrow macrophages

“…Expression of Wnt7b can be induced by PTH, has been shown to increase with osteoblastic differentiation and to increase bone mass as well as osteoblast number in vivo [29]. Wnt10b is an important factor in coupling the actions of osteoblasts and osteoclasts, while also being able to enhance commitment to the osteoblastic lineage [30, 31]. In contrast, the expression of Wnt5a , reported to antagonize canonical Wnt signaling by stimulating destruction of β-catenin via GSK3β [32], was unaffected by PTH treatment in both WT and KO CM treated groups (Fig.…”