In addition to Wnt and RANK-RANKL-OPG signaling, two cytokines play essential signaling roles in bone remodeling: macrophage colony-stimulating factor (MCSF) and TGF-β. MCSF stimulates osteoclasto-genesis by binding to monocyte progenitor cells and preosteoclasts. This triggers intracellular cascades that induce NFATc1, the main transcription factor for osteoclastogenesis . The importance of MCSF stems from its role in stimulating the first stage of osteoclastogenesis (Figure ), which RANKL does not stimulate, and the proliferation of osteoclast precursor cells. The role of TGF-β is less straightforward. Its regulatory effects are concentration dependent . Moreover, it regulates both bone formation and bone resorption. Low concentrations of TGF-β stimulate osteoclast production while promoting preosteoblast migration and proliferation. High concentrations inhibit osteoclastogenesis. Also, high concentrations inhibit preosteoblast migration and late-stage osteoblast differentiation. Although these contradictory findings still puzzle researchers, the mechanism of changes in TGF-β concentration during remodeling is well understood. Inactive TGF-β is stored in the extracellular matrix of bone . As osteoclasts remove bone, TGF-β is released and activated, increasing the concentration of TGF-β .