SUMMARY 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 animal 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 (BMSCs) to the bone resorptive sites and that this process is mediated through SMAD signaling pathway. Analysis of a mouse model carrying a CED-derived TGF-β1 mutation, which exhibits the typical progressive diaphyseal dysplasia with tibial fractures, 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 the bone remodeling diseases.

Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone matrix, regulates bone mass in adulthood. We report that IGF-1 released from bone matrix stimulates osteoblastic differentiation of mesenchymal stem cell (MSCs) by activation of mTOR during bone remodeling. Mice knockout of IGF-1 receptor (Igf1r) in the preosteoblastic cells exhibited low bone mass and reduced mineral deposition rates. The MSCs recruited to the bone surface were unable to differentiate into osteoblasts. In age-related osteoporosis in humans, we found that marrow IGF-1 levels were 40% lower than controls. Similarly, the levels of IGF-1 in the bone matrix and marrow of aged rats were also decreased and directly correlated with the age-related decrease in bone mass. Notably, injection of IGF-1 with IGF binding protein 3 (IGFBP3), not IGF-1 alone, increased the level of IGF-1 in the bone matrix and stimulated new bone formation in old rats. Thus, IGF-1 released during bone resorption from bone matrix activates mTOR to induce osteoblast differentiation of MSCs in maintaining bone micro-architecture and mass.