Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis. However, the underlying mechanism is still not completely understood. In this study, progranulin (PGRN) was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening. In addition, PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model. Furthermore, estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN. Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling. In addition, loss of PGRN led to the reduction of estrogen receptor α, the important estrogen receptor involved in estrogen regulation of osteoporosis, through enhancing its degradation via K48-linked ubiquitination. These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptor α.

雌激素缺乏被认为是绝经后骨质疏松症的最重要原因。然而，其根本机制仍不完全清楚。在这项研究中，通过高通量蛋白质组学筛选，分离出颗粒体蛋白前体（PGRN）作为绝经后妇女骨矿物质密度的关键调节剂。此外，在卵巢切除诱导的骨质疏松模型中，PGRN 缺陷小鼠的骨量显着低于其同窝小鼠。此外，雌激素介导的破骨细胞生成和骨吸收抑制及其对卵巢切除引起的骨质流失的保护在很大程度上取决于 PGRN。机制研究揭示了 PGRN 和雌激素信号之间存在正反馈调节环。此外，PGRN 的缺失导致雌激素受体 α 的减少，雌激素受体 α 是参与骨质疏松症雌激素调节的重要雌激素受体，通过 K48 连接的泛素化增强其降解。这些发现不仅提供了PGRN和雌激素信号在调节破骨细胞生成和骨质疏松症中以前未被认识的相互作用，而且还可能为通过靶向PGRN/雌激素受体α来预防和治疗绝经后骨质疏松症提供一种新的治疗方法。