# Estradiol regulates osteoclast sialylation via ST3Gal1 in postmenopausal osteoporosis

## TL;DR

This study shows how estradiol prevents excessive bone loss after menopause by regulating a sialylation pathway in osteoclasts.

## Contribution

The study identifies ST3GAL1 as a key mediator linking estrogen signaling to osteoclast activity in postmenopausal osteoporosis.

## Key findings

- Estrogen-bound ERα suppresses RANKL-induced ST3GAL1 expression via c-FOS.
- Postmenopausal osteoporotic patients have elevated serum sialic acid levels.
- Sialidase treatment reduces osteoclast-mediated bone loss in estrogen-deficient models.

## Abstract

Estrogen deficiency after menopause accelerates bone loss by stimulating osteoclast formation and activity, but the molecular pathways that link estrogen signaling to osteoclast regulation remain incompletely defined. Here, we identify the sialyltransferase ST3GAL-I as a key mediator of RANKL-induced osteoclastogenesis. RANKL activates c-FOS to drive ST3GAL1 transcription, whereas estrogen-bound ERα competes with TRAF6 and suppresses this c-FOS–dependent induction. In a clinical cohort of pre-menopausal and post-menopausal women with or without osteoporosis, serum total and α-2,3-linked sialic acid levels increased with age and were highest in post-menopausal osteoporotic patients. Single-cell RNA sequencing of human bone revealed that osteoclasts form a prominent cluster only after menopause, where FOS, CTSK, and ST3GAL1 are strongly co-expressed, and the estrogen-responsive gene PGR is down-regulated. Additionally, in vivo experiments showed that sialidase treatment in estrogen-deficient models effectively reduced osteoclast-mediated bone loss, mimicking the effects of estradiol. These findings define a direct molecular link between loss of estrogen and activation of a FOS–ST3GAL1 sialylation pathway in osteoclasts, providing mechanistic insight into the enhanced bone resorption characteristic of post-menopausal osteoporosis.