The transient receptor potential vanilloid type 4 ion channel (TRPV4) is known to play an important role in the regulation of pain and inflammation. Pharmacological ligands of TRPV4 regulate human osteoclast formation in vitro, but the effects of these agents on osteoblast function have not been studied and their effects on bone loss in vivo are unknown. Here it was reviewed the effects of the TRPV4 mutants on mouse osteoclast and osteoblast differentiation in vitro and in vivo. The constitutive active mutants activated osteoclast formation and bone resorption in a dose dependent manner in bone marrow–osteoblast co-cultures and receptor activator of NFκB ligand-generated osteoclast cultures. We also discussed here that the constitutively active TRPV4 mutants induced bone loss in mice, with histomorphometric analysis showing activating effects on indices of bone resorption and bone formation. The chondrocyte differentiation factor SOX9 also seems to be in association with chondrocyte-like cells, suggesting that TRPV4 regulates the SOX9 pathway and contributes to the process of chondrogenesis. Furthermore, it seems to be possible that the pharmacological blockade of TRPV4 ion channels by small chemicals may inactivate osteoclastic bone resorption and protect against future bone loss.