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

## TL;DR

This study shows that HSD17B7 helps prevent bone loss in estrogen deficiency by stabilizing the estrogen receptor and is essential for the effectiveness of the drug raloxifene.

## Contribution

HSD17B7 is identified as a novel coactivator of ERα that stabilizes it and mediates the therapeutic effect of raloxifene in osteoporosis.

## Key findings

- HSD17B7 interacts with ERα and prevents its degradation, increasing ERE activity.
- HSD17B7 deficiency in preosteoclasts worsens bone loss in estrogen-deficient mice.
- Raloxifene's protective effect on bone is lost without HSD17B7, highlighting its mediating role.

## Abstract

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.

In this study, we identified a previously unrecognized function of HSD17B7 as an ERα‐binding protein that serves as a coactivator to influence trabecular bone mass in estrogen deficiency. Specifically, deleting HSD17B7 in myeloid cells enhanced the number of osteoclasts and decreased trabecular bone mass post‐OVX, compared with control OVX, mirroring observations in myeloid ERα KO mice. During increased bone resorption, HSD17B7 expression levels paralleled those of ERα in preosteoclasts. However, HSD17B7 ablation accelerated bone resorption, as evidenced by elevated mitochondrial content and oxidative capacity in preosteoclasts. A transcriptome analysis combined with physiological data pinpointed PLD1 as the target through which HSD17B7 modulates mitochondrial OxPhos, aligning with previous research that highlighted the crucial role of the PLD1 and mTOR signaling pathway in metabolism. An analysis of human subjects revealed that preosteoclasts from severely osteoporotic patients exhibited lower expression levels of HSD17B7 and ERα than those from controls, suggesting that HSD17B7 acts as a positive regulator in human osteoporosis. Lastly, we demonstrated that the selective ER modulator raloxifene had no therapeutic effect on estrogen deficiency‐induced osteoporosis in cKO mice. Therefore, raloxifene's inhibitory effect on osteoclast activation is mediated through HSD17B7, which emphasizes the importance of the HSD17B7–ERα regulatory mechanism in bone homeostasis.