mTOR signaling in skeletal development and disease

Abstract

The mammalian/mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that integrates inputs from nutrients and growth factors to control many fundamental cellular processes through two distinct protein complexes mTORC1 and mTORC2. Recent mouse genetic studies have established that mTOR pathways play important roles in regulating multiple aspects of skeletal development and homeostasis. In addition, mTORC1 has emerged as a common effector mediating the bone anabolic effect of Igf1, Wnt and Bmp. Dysregulation of mTORC1 could contribute to various skeletal diseases including osteoarthritis and osteoporosis. Here we review the current understanding of mTOR signaling in skeletal development and bone homeostasis, as well as in the maintenance of articular cartilage. We speculate that targeting mTOR signaling may be a valuable approach for treating skeletal diseases.

Fig. 1. A schematic of mTORC1 and mTORC2 signaling.

Dashed line denotes partial inhibition of mTORC2 by Rapamycin upon prolonged treatment

Fig. 2. Multiple growth factors activate mTORC1 to stimulate osteoblast differentiation and activity.

Curved arrows denote proliferation. MP mesenchymal progenitor, PreOB preosteoblast targeted by Osx-Cre, OB osteoblast

Fig. 3. mTORC2 is a common mediator for mechanical and biochemical signals to stimulate osteoblast differentiation.

mTORC2 signaling also inhibits (denoted by blocked arrow) adipocyte differentiation from bipotential mesenchyaml progenitors (MP)