Activation of mTORC1 in B Lymphocytes Promotes Osteoclast Formation via Regulation of β-Catenin and RANKL/OPG

Abstract

The cytokine receptor activator of nuclear factor-κB ligand (RANKL) induces osteoclast formation from monocyte/macrophage lineage cells. However, the mechanisms by which RANKL expression is controlled in cells that support osteoclast differentiation are still unclear. We show that deletion of TSC1 (tuberous sclerosis complex 1) in murine B cells causes constitutive activation of mechanistic target of rapamycin complex 1 (mTORC1) and stimulates RANKL but represses osteoprotegerin (OPG) expression and subsequently promotes osteoclast formation and causes osteoporosis in mice. Furthermore, the regulation of RANKL/OPG and stimulation of osteoclastogenesis by mTORC1 was confirmed in a variety of RANKL-expressing cells and in vivo. Mechanistically, mTORC1 controls RANKL/OPG expression through negative feedback inactivation of Akt, destabilization of β-catenin mRNA, and downregulation of β-catenin. Our findings demonstrate that mTORC1 activation-stimulated RANKL expression in B cells is sufficient to induce bone loss and osteoporosis. The study also established a link between mTORC1 and the RANKL/OPG axis via negative regulation of β-catenin. © 2016 American Society for Bone and Mineral Research.

Keywords: B LYMPHOCYTE; OSTEOCLAST FORMATION; RANKL (RECEPTOR ACTIVATOR OF NUCLEAR FACTOR-κB LIGAND); mTORC1 (MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1); β-CATENIN.