KitW-sh Mutation Prevents Cancellous Bone Loss during Calcium Deprivation

• Published in: Calcified tissue international 2018, Vol.102 (1), p.93-104
• Main Authors: Lotinun, Sutada, Suwanwela, Jaijam, Poolthong, Suchit, Baron, Roland
• Format: Article
• Language: English
• Subjects: Biochemistry; Biomedical and Life Sciences; Cell Biology; Endocrinology; Life Sciences; Original Research; Orthopedics
• ISSN: 0171-967X; 1432-0827
• DOI: 10.1007/s00223-017-0334-8

Calcium is essential for normal bone growth and development. Inadequate calcium intake increases the risk of osteoporosis and fractures. Kit ligand/ c - Kit signaling plays an important role in regulating bone homeostasis. Mice with c - Kit mutations are osteopenic. The present study aimed to investigate whether impairment of or reduction in c - Kit signaling affects bone turnover during calcium deprivation. Three-week-old male WBB6F1/J- Kit W /Kit W - v / J ( W/W v ) mice with c - Kit point mutation, Kit W - sh /HNihrJaeBsmJ ( W sh /W sh ) mice with an inversion mutation in the regulatory elements upstream of the c - Kit promoter region, and their wild-type controls (WT) were fed either a normal (0.6% calcium) or a low calcium diet (0.02% calcium) for 3 weeks. μCT analysis indicated that both mutants fed normal calcium diet had significantly decreased cortical thickness and cancellous bone volume compared to WT. The low calcium diet resulted in a comparable reduction in cortical bone volume and cortical thickness in the W/W v and W sh /W sh mice, and their corresponding controls. As expected, the low calcium diet induced cancellous bone loss in the W/W v mice. In contrast, W sh /W sh cancellous bone did not respond to this diet. This c - Kit mutation prevented cancellous bone loss by antagonizing the low calcium diet-induced increase in osteoblast and osteoclast numbers in the W sh /W sh mice. Gene expression profiling showed that calcium deficiency increased Osx, Ocn, Alp, type I collagen, c-Fms, M-CSF, and RANKL/OPG mRNA expression in controls; however, the W sh mutation suppressed these effects. Our findings indicate that although calcium restriction increased bone turnover, leading to osteopenia, the decreased c - Kit expression levels in the W sh /W sh mice prevented the low calcium diet-induced increase in cancellous bone turnover and bone loss but not the cortical bone loss.