Neddylation of NFATc1 and Runx2 regulates osteoclast-osteoblast balance and represents a dual-action therapeutic target for postmenopausal osteoporosis.

Postmenopausal osteoporosis (PMOP) arises from a bone remodeling imbalance in which osteoclast-mediated resorption exceeds osteoblast-driven formation. However, current therapies primarily target osteoclasts without restoring osteoblast function, underscoring the need for mechanism-driven dual-action approaches. Here, we identify neddylation as a post-translational modification that reciprocally regulates osteoclast and osteoblast differentiation. In bone tissue from patients with PMOP, NEDD8 and its activating enzyme NAE1 were significantly upregulated, indicating heightened pathway activity. Mechanistically, c-Cbl neddylates NFATc1 to promote osteoclastogenesis, whereas Rbx1 neddylates Runx2 to suppress osteoblast maturation. Pharmacological blockade with the NAE1 inhibitor MLN4924 counteracted both effects and, in ovariectomized mice, reduced osteoclast activity while preserving osteoblast function, preventing deterioration of bone mass and microarchitecture. In human PMOP bone tissues, elevated NEDD8 and NAE1 expression was associated with increased NFATc1 in osteoclast-lineage cells and reduced Runx2 in osteoblast-lineage cells, suggesting translational relevance. These findings reveal neddylation as a unifying mechanism that coordinates opposing effects on osteoclast and osteoblast master transcription factors and highlight its potential as a mechanism-driven dual-action therapeutic target.