PHF2-mediated hydroxylation destabilizes NFATc1 to restrain osteoclastogenesis

Abstract Osteoclast differentiation requires not only the induction of osteoclastogenic gene expression but also the removal of inhibitory regulators that limit lineage progression. Although transcriptional brakes on osteoclastogenesis have been described, whether post-translational brakes similarly limit NFATc1 accumulation remains unclear. Here, we identify plant homeodomain finger protein 2 (PHF2), a Jumonji C (JmjC) domain-containing lysine demethylase, as a post-translational brake on osteoclast differentiation and osteoclast-driven bone loss. PHF2 expression progressively declined during RANKL-induced osteoclastogenesis, whereas myeloid-specific Phf2 deletion enhanced osteoclast formation and trabecular bone loss. Conversely, PHF2 gain-of-function suppressed osteoclast differentiation. PHF2 directly associated with NFATc1 and catalyzed K612 hydroxylation in vitro, facilitating HUWE1-dependent ubiquitination and proteasomal degradation of NFATc1. Consistent with this mechanism, the K612A substitution stabilized NFATc1 and enhanced osteoclastogenesis. In an ovariectomy model of postmenopausal osteoporosis, myeloid Phf2 deficiency further aggravated trabecular bone deterioration and osteoclast activity in vivo. Collectively, these findings identify the PHF2–NFATc1–HUWE1 axis as a previously unrecognized post-translational brake on osteoclast differentiation, with mechanistic implications for osteoclast-driven bone loss.