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

Area of Science:

• Endocrinology
• Molecular Biology
• Bone Biology

Background:

• Estrogen receptor alpha (ERα) is crucial for regulating osteoclasts and bone density, particularly in estrogen deficiency.
• The precise mechanisms governing ERα interactions with coactivators remain incompletely understood.
• Understanding these interactions is key to developing treatments for osteoporosis.

Purpose of the Study:

• To identify novel proteins interacting with ERα.
• To elucidate the role of HSD17B7 in ERα regulation and its impact on estrogen-deficient osteoporosis.
• To explore HSD17B7 as a potential therapeutic target.

Main Methods:

• Protein-protein interaction screening using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS).
• Analysis of ERα degradation pathways and ERE activity.
• Assessment of bone loss in HSD17B7-deficient mice models.
• Investigation of preosteoclasts from osteoporosis patients.

Main Results:

• Identified a physical interaction between HSD17B7 and ERα, with ERα binding to the 119-172 domain of HSD17B7.
• This interaction inhibits ERα degradation and enhances ERE activity.
• HSD17B7 deficiency in preosteoclasts exacerbates bone loss in estrogen-deficient mice, linked to PLD1-mTOR signaling and mitochondrial biogenesis.
• Reduced HSD17B7 and ERα expression observed in preosteoclasts from severe osteoporosis patients.
• Raloxifene efficacy in preventing bone loss is dependent on HSD17B7 presence.

Conclusions:

• HSD17B7 stabilizes ERα, playing a critical role in preventing bone loss during estrogen deficiency.
• HSD17B7-mediated regulation of ERα represents a novel therapeutic strategy for estrogen-deficient osteoporosis.
• Targeting HSD17B7 offers a promising avenue for osteoporosis treatment.