HSD17B7 counters bone loss in estrogen deficiency via estrogen receptor stabilization and mediates the effect of raloxifene

Estrogen receptor (ER) α is a key regulator of osteoclasts in osteoporosis induced by estrogen deficiency. Although ERα is regulated through interactions with various coactivators, the precise mechanisms remain unknown. We used LC-MS/MS to screen proteins that bind to ERα and identified a physical interaction between HSD17B7 and ERα, specifically that ERα binds to the 119–172 domain of HSD17B7. This interaction blocked ubiquitin-proteasomal degradation of ERα and increased ERE activity. Estrogen-deficient mice lacking HSD17B7 in their preosteoclasts showed more severe bone loss than control mice. This was attributed to increased mitochondrial biogenesis through the activation of PLD1-mTOR signaling. Additionally, in preosteoclasts derived from patients with severe osteoporosis, HSD17B7 and ERα expressions were significantly reduced, compared with control subjects. Finally, raloxifene, which boosts ERα, did not inhibit bone loss without HSD17B7, confirming the modulation of ERα through HSD17B7. Therefore, HSD17B7 regulation is a novel therapeutic approach for alleviating estrogen-deficient osteoporosis.