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Bone Abstracts (2016) 5 P176 | DOI: 10.1530/boneabs.5.P176

ECTS2016 Poster Presentations Cell biology: osteoclasts and bone resorption (35 abstracts)

Impaired c-kit signaling couples bone resorption to bone formation through wnt10b in kitw-Sh/W-Sh mice

Sutada Lotinun 1, , Nateetip Krishnamra 3 & William Horne 2

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1Department of Physiology and STAR on Craniofacial and Skeletal Disorders, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; 2Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA; 3Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.


Kit ligand/c-Kit receptor tyrosine kinase complex has been implicated as a target for bone remodeling process. Loss of function mutation in c-Kit causes low bone mass in KitW/W-v (W/Wv) mice. However, these mice are sterile and it is unclear whether the observed skeletal phenotype is secondary to sex hormone deficiency. To address this question, the skeletal phenotype of KitW-sh/W-sh (Wsh/Wsh) mice, which are fertile, was identified. Wsh/Wsh mice, which carried an inversion mutation affecting the transcriptional regulatory elements upstream of the c-Kit promoter region, exhibited osteopenia with elevated bone resorption and bone formation. Histomorphometry indicated an increase in osteoclast number, bone formation rate and mineral apposition rate at 6 and 9 weeks old. c-Kit mutation increased osteoclast differentiation. FACS analysis indicated an increase in the percentage of c-Fms+CD11b+ cells in spleen of Wsh/Wsh mice compared to controls. In primary osteoblast culture, Wsh/Wsh osteoblasts had increased number of committed osteoblast progenitors, alkaline phosphatase and mineralized bone nodules. These changes were associated with increases in steady-state mRNA levels for osteoblast marker genes, including osteocalcin, Osterix, alkaline phosphatase, type I collagen and Runx2, in femurs. c-Kit was expressed in both osteoclasts and osteoblasts and mutation of c-Kit decreased its expression level in Wsh/Wsh osteoclasts but not osteoblasts, suggesting an indirect effect of c-Kit on bone formation. Osteoclast-derived coupling factor Wnt10b mRNA was increased in Wsh/Wsh osteoclasts. Wsh/Wsh osteoclasts produced elevated Wnt10b protein level. Antagonizing Wnt10b with Wnt inhibitor DKK1 reduced Wsh/Wsh osteoclast conditioned medium-induced alkaline phosphatase activity and mineralization in osteoblast cultures. Our data suggest that c-Kit is a negative regulator of bone turnover, and that increased bone formation following disruption of c-Kit signaling is driven by osteoclast-derived Wnt 10b.

Volume 5

43rd Annual European Calcified Tissue Society Congress

Rome, Italy
14 May 2016 - 17 May 2016

European Calcified Tissue Society 

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