LSD1 metabolically integrates osteoclast differentiation and inflammatory bone resorption through HIF ‐1α and E2F1

Objective Hypoxia occurs in tumors, infections, and inflammatory sites such as joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. We showed that LSD1 metabolically integrates inflammatory osteoclastogenesis and bone resorption. Methods LSD1 specific inhibitors and siRNAs were used to inhibit LSD1. Using human osteoclast precursors derived from CD14+ cells, RNA-sequencing and subsequent analysis were performed. Accelerated bone loss and inflammatory osteolysis models were tested as mice model. After cis-expression quantitative trait locus (cis-eQTL) analysis for HIF-1α, the association between HIF-1α allelic variants bone erosion was evaluated in RA patients. Results RANKL induces LSD1 expression in an mTOR-dependent manner. The expression of LSD1 was higher in RA synovium than that from osteoarthritis. LSD1 inhibition suppresses osteoclast differentiation. Transcriptome analysis identified LSD1-mediated hypoxia and cell-cycle pathways during human osteoclastogenesis. Furthermore, HIF-1α protein, which is rapidly degraded by the proteasome in normoxia, was expressed in RANKL-stimulated osteoclast precursor cells. RANKL-induced LSD1 stabilized HIF-1α protein, thereby promoted glycolysis, along with E2F1, which was also upregulated by LSD1. cis-eQTL analysis revealed that higher HIF-1α expression was associated with increased bone erosion in RA. LSD1 inhibition decreased pathological bone resorption in an accelerated osteoporosis mouse model and arthritis and inflammatory osteolysis mouse models. Conclusion LSD1 metabolically regulates osteoclastogenesis in an inflammatory energy-demanding environment and provides new therapeutic strategies targeting osteoclasts against inflammatory arthritis including RA.