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c-Kit tyrosine kinase receptor has been identified as a regulator of bone homeostasis. The  c-Kit  loss-of-function mutations in WBB6F1/J- Kit   W/W-v   mice result in low bone mass. However, these mice are sterile and it is unclear whether the observed skeletal phenotype is secondary to a sex hormone deficiency. In contrast, C57BL/6J- Kit   W-sh  /  W-sh   ( W   sh   /W   sh  ) mice, which carry an inversion mutation affecting the transcriptional regulatory elements of the  c-Kit  gene, are fertile. Here, we showed that  W   sh   /W   sh   mice exhibited osteopenia with elevated bone resorption and bone formation at 6- and 9-week-old. The  c-Kit W   sh   mutation increased osteoclast differentiation, the number of committed osteoprogenitors, alkaline phosphatase activity and mineralization.  c-Kit  was expressed in both osteoclasts and osteoblasts, and  c-Kit  expression was decreased in  W   sh   /W   sh  osteoclasts, but not osteoblasts, suggesting an indirect effect of  c-Kit  on bone formation. Furthermore, the osteoclast-derived coupling factor Wnt10b mRNA was increased in  W   sh   /W   sh   osteoclasts. Conditioned medium from  W   sh   /W   sh   osteoclasts had elevated Wnt10b protein levels and induced increased alkaline phosphatase activity and mineralization in osteoblast cultures. Antagonizing Wnt10b signaling with DKK1 or Wnt10b antibody inhibited these effects. Our data suggest that  c-Kit  negatively regulates bone turnover, and disrupted  c-Kit  signaling couples increased bone resorption with bone formation through osteoclast-derived Wnt 10 b.

Disruption of c-Kit Signaling in KitW-sh/W-sh Growing Mice Increases Bone Turnover