Editors' ChoiceBone

Model Remodeling-Osteocytes Take Center Stage

See allHide authors and affiliations

Science Translational Medicine  21 Sep 2011:
Vol. 3, Issue 101, pp. 101ec152
DOI: 10.1126/scitranslmed.3003211

Bones are under constant renovation by a demolition crew of osteoclasts and a team of osteoblasts, the bone builders. Working together, these cells usually maintain healthy, stable bone. But sometimes overactive osteoclasts disrupt this teamwork, resorbing too much bone and giving rise to common bone disorders such as osteoporosis and Paget’s disease. The receptor activator of NF-κB ligand (RANKL) molecule is required for osteoclast formation, and osteoblast expression of RANKL has been thought to drive this process, coupling bone deposition with bone resorption. However, new data now indicate that RANKL expression in another bone cell type, the osteocyte, is the primary regulator in bone remodeling.

Because RANKL is expressed by several cell types, Nakashima et al. sought to better characterize the source and action of RANKL in bone. They focused on osteoblast-derived osteocytes, specialized mechanosensory cells that are embedded in the bony matrix and are thus uniquely poised to mediate bone remodeling under stress. By generating a mouse whose osteocytes expressed the fluorescent tag GFP, the authors were able to improve conventional bone cell isolation and recover purified GFP+ osteocytes by flow cytometry. The purified osteocytes exhibited a 10 times higher level of RANKL and induced osteoclast formation in culture much better than GFP osteoblasts. Extending these studies in vivo, they engineered mice that lacked RANKL only in osteocytes. Although no phenotype was evident at birth, as they grew, these osteocyte-specific RANKL-deficient mice exhibited increased bone volume and mass, with decreased numbers of osteoclasts, indicating that osteocyte RANKL is critical for postnatal bone remodeling and formation of osteoclasts. Nakashima et al. conclude that osteocytes and not osteoblasts are the primary mediators of RANKL-dependent bone remodeling and osteoclast formation. In an independent, simultaneously published study, Xiong et al. confirm these conclusions using elegant and systematic inactivation of RANKL in several cell populations from the mouse.

The osteocyte’s new role as a central regulator of bone remodeling represents a shift in the current paradigm of bone homeostasis. Verifying these findings in human bone will be important for how we evaluate treatment responses in osteoporosis and for improving drug therapies, especially because denosumab, a RANKL inhibitor, is now used in the treatment of osteoporosis.

T. Nakashima et al., Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 11 September 2011 (10.1038/nm.2452). [Abstract]

J. Xiong et al., Matrix-embedded cells control osteoclast formation. Nat. Med. 11 September 2011 (10.1038/nm.2448). [Abstract]

Stay Connected to Science Translational Medicine

Navigate This Article