HSD17B7 Counters Bone Loss in Estrogen Deficiency via Estrogen Receptor Stabilization and Mediates the Effect of Raloxifene.

Estrogen receptor (ER) α is a central regulator of osteoclasts in osteoporosis induced by estrogen deficiency. ERα is regulated through interactions with various coactivators; however, the precise mechanisms of these interactions are not yet fully understood. We screened for proteins that bind to ERα using LC-MS/MS and identified a physical interaction between HSD17B7 and ERα, specifically ERα binding 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, the expression of HSD17B7 and ERα was significantly reduced compared to the 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.