TGF-β1–induced migration of bone mesenchymal stem cells couples bone resorption with formation

Abstract

Bone is a dynamic tissue and requires the precise coordination of formation with loss. Here, Xu Cao and his colleagues show that the bone-chewing activity of osteoclasts results in the local release of active TGF-β1 from the surface of the bone, inducing the migration of nearby bone-forming osteoblastic progenitor cells to this resorbed region. In this manner, proper matching of the localized rates of bone loss and bone creation is ensured ( pages 729–731 ). Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and in vivo models that active TGF-β1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to the bone resorptive sites and that this process is mediated through a SMAD signaling pathway. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF-β1), which show the typical progressive diaphyseal dysplasia seen in the human disease, we found high levels of active TGF-β1 in the bone marrow. Treatment with a TGF-β type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-β1 functions to couple bone resorption and formation, modulation of TGF-β1 activity could be an effective treatment for bone remodeling diseases.