Inositol Polyphosphate 4-Phosphatase B as a Regulator of Bone Mass in Mice and Humans

Osteoporosis is a multifactorial genetic disease characterized by reduction of bone mass due to dysregulation of osteoclast differentiation or maturation. Herein, we identified a regulator of osteoclastogenesis, the murine homolog of inositol polyphosphate 4-phosphatase type II alpha (Inpp4b alpha). Expression of Inpp4b alpha is detected from early osteoclast differentiation to activation stage. Targeted expression of native Inpp4b alpha ex vivo repressed whereas phosphatase-inactive Inpp4b alpha stimulated osteoclast differentiation. Inpp4b alpha 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.