1. Inositol Polyphosphate 4-Phosphatase B as a Regulator of Bone Mass in Mice and Humans
- Author
-
Marina V. Kisseleva, Mathieu Ferron, François Rousseau, Michel Arsenault, Monica Pata, Sylvie Giroux, Philip W. Majerus, Mohamed Rached, Latifa Elfassihi, Maya Boudiffa, and Jean Vacher
- Subjects
medicine.medical_specialty ,Bone density ,Physiology ,Cellular differentiation ,Down-Regulation ,Osteoclasts ,chemistry.chemical_element ,Calcium ,Biology ,Article ,Calcium in biology ,Mice ,chemistry.chemical_compound ,Bone Density ,Osteoclast ,Internal medicine ,medicine ,Animals ,Humans ,Protein Isoforms ,Inositol ,Molecular Biology ,NFATC Transcription Factors ,Cell Differentiation ,Cell Biology ,Phosphoric Monoester Hydrolases ,Cell biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Osteoporosis ,Signal transduction ,Signal Transduction - Abstract
Osteoporosis is a multifactorial genetic disease characterized by reduction of bone mass due to dysregulation of osteoclast differentiation or maturation. Herein, we identified a novel regulator of osteoclastogenesis, the murine homologue of inositol polyphosphate 4-phosphatase type IIa (Inpp4bα). Expression of Inpp4bα is detected from early osteoclast differentiation to activation stage. Targeted expression of native Inpp4bα ex-vivo repressed whereas phosphatase-inactive Inpp4ba stimulated osteoclast differentiation. Inpp4bα acts on intracellular calcium level that modulates NFATc1 nuclear translocation and activation. In vivo mice deficient in Inpp4b displayed increased osteoclast differentiation rate and potential resulting in decreased bone mass and osteoporosis. Importantly, INPP4B in human was identified as a susceptibility locus for osteoporosis. This study defined Inpp4b as a major modulator of the osteoclast differentiation and as a gene linked to variability of bone mineral density in mice and humans.
- Full Text
- View/download PDF