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Updated: Mar 16, 2026
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Disruption of c-Kit Signaling in Kit(W-sh/W-sh) Growing Mice Increases Bone Turnover
Sutada Lotinun1,2, Nateetip Krishnamra3
1Department of Physiology and STAR on Craniofacial and Skeletal Disorders, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
Abstract:
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.
Insights
Disrupted c-Kit signaling in mice leads to osteopenia by increasing bone turnover. This occurs via enhanced osteoclast activity and elevated Wnt10b, coupling bone resorption with formation.
Area of Science:
- Bone Biology
- Cell Signaling
- Endocrinology
Background:
- The c-Kit tyrosine kinase receptor plays a role in bone homeostasis.
- Loss-of-function mutations in c-Kit in mice lead to low bone mass, but these mice are sterile, confounding skeletal phenotype assessment.
- Fertile mice with a c-Kit transcriptional regulatory mutation (W(sh)/W(sh)) provide a model to study c-Kit's role in bone turnover.
Purpose of the Study:
- To investigate the role of c-Kit signaling in regulating bone turnover in fertile mice.
- To determine the mechanisms by which c-Kit mutations affect bone resorption and formation.
- To explore the potential involvement of Wnt signaling in c-Kit-mediated bone regulation.
Main Methods:
- Analysis of bone phenotype in W(sh)/W(sh) mice at 6 and 9 weeks of age.
- Assessment of osteoclast differentiation, osteoblast activity (alkaline phosphatase, mineralization), and c-Kit expression in bone cells.
- Measurement of Wnt10b mRNA and protein levels in osteoclasts and its effect on osteoblasts in vitro.
- Inhibition of Wnt10b signaling using DKK1 or Wnt10b antibody.
Main Results:
- W(sh)/W(sh) mice exhibit osteopenia with increased bone resorption and formation.
- The c-Kit mutation enhances osteoclast differentiation and osteoblast activity.
- c-Kit expression is reduced in W(sh)/W(sh) osteoclasts, suggesting an indirect effect on bone formation.
- Osteoclast-derived Wnt10b is upregulated in W(sh)/W(sh) mice and promotes osteoblast activity.
- Blocking Wnt10b signaling mitigates the effects of the c-Kit mutation on bone cells.
Conclusions:
- c-Kit negatively regulates bone turnover.
- Disrupted c-Kit signaling couples increased bone resorption with bone formation through osteoclast-derived Wnt10b.
- This study elucidates a novel mechanism linking c-Kit, Wnt10b, and bone remodeling balance.
