The many ways of osteoclast activation.

Osteoclasts are the cells responsible for bone resorption, a process that is essential for the maintenance of healthy bones. Bone diseases, such as osteoporosis, which are characterized by high rates of bone resorption and loss of bone mass, may benefit from treatments that inhibit osteoclast formation and/or function. The RANKL/RANK pathway is critical for both osteoclast formation and function, and these effects are thought to be mediated by the transcription factor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). In this issue of the JCI, Bae et al. challenge the convention that NFATc1 is the sole critical regulator of RANKL/RANK-dependent osteoclast activation. Specifically, the authors show that MYC drives metabolic reprogramming in osteoclasts and that MYC induces estrogen receptor-related receptor α (ERRα) to regulate osteoclastogenesis. Importantly, both loss of MYC and pharmacological inhibition of ERRα attenuated bone loss in a mouse model of osteoporosis. Together, the results of this study suggest that the MYC/ERRα pathway should be further explored as a drug target for bone diseases.