Pim1 promotes the maintenance of bone homeostasis by regulating osteoclast function.

Abstract

The Pim1 (proviral integration site for Moloney leukemia virus 1) protein is a serine/threonine kinase that is essential for cell proliferation, apoptosis and innate immune responses. Here we show that Pim1 promotes osteoclast resorptive function without affecting osteoclast numbers. Specifically, we found that mice lacking Pim1 (Pim1^-/-) developed increased trabecular bone mass and indices such as trabecular bone-mass density. This was due to the direct phosphorylation of TRAF6 by Pim1 in mature osteoclasts, which activated the Akt-GSK3β signaling pathway. This, in turn, promoted the acetylation and consequent stabilization of microtubules, which permitted the formation of the osteoclast sealing zone. In vivo experiments then showed that, when mice with lipopolysaccharide-induced bone loss or tumor-induced osteolysis were treated with SGI-1776, a Pim1 inhibitor that is more selective for Pim1, the bone loss was significantly ameliorated. Thus, Pim1 plays an important role in osteoclast function and may be a therapeutic target for bone-related diseases.