Osteocyte connexin hemichannels and prostaglandin E2 release dictate bone marrow mesenchymal stromal cell commitment

• 成果类型: Article
• 署名作者: Zhang, Jingruo; Acosta, Francisca M.; Wang, Xuewei; Zhao, Dezhi; Zhang, Lidan; Hua, Rui; Guo, Qianjin; Zhong, Leilei; Qin, Ling; Riquelme, Manuel A.; Jiang, Jean X.
• 署名单位: University of Texas System; University of Texas at San Antonio; University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14329
• DOI: 10.1073/pnas.2412144122
• 发表日期: 2025-02-18
• 关键词: stem-cells; adipose-tissue; differentiation; channels; protocol; culture; apoptosis; biology; obesity; pge(2)

摘要

Bone is a dynamic organ constantly undergoing remodeling with both bone formation and resorption. Bone formation is mediated by osteoblasts originating from the differentiation of bone marrow (BM) mesenchymal stem and progenitor cells (BM- MSPCs). However, how bone cells communicate with BM-MSPCs to coordinate bone formation remains largely elusive. Here, we unveil a key role of osteocyte connexin 43 (Cx43) hemichannels in regulating the lineage commitment of BM- MSPCs. Two transgenic mouse models expressing dominant negative Cx43 mutants in osteocytes were used: R76W (inhibiting gap junctions) and O130 to 136 (inhibiting both hemichannels and gap junctions). BM-MSPCs from O130 to 136 mice showed enhanced adipogenic differentiation and reduced osteogenic potential, leading to increased BM adipocytes. Flow cytometry and single- cell RNA sequencing revealed shifts in BM-MSPC subsets, less osteogenic- biased MSPCs, and more adipogenic- biased MSPCs in O130 to 136 mice. Conversely, R76W, with more functional hemichannels, exhibited effects similar to WT mice or even greater opposite effects than O130 to 136 mice. Prostaglandin E2 (PGE2), released from active Cx43 hemichannels, inhibited adipogenesis and promoted osteogenesis via the PGE2 receptor EP4 and ERK1/2 signaling. Inhibition of Cx43 hemichannels or EP4 led to increased adipogenic- biased MSPCs. Moreover, administration of a Cx43(M1) antibody, which inhibits hemichannels, substantially increased BM adipocytes, accompanied by increased adipogenic- biased MSPCs, and decreased osteogenic- biased MSPCs. Our study highlights the pivotal role of osteocyte Cx43 hemichannels in BM-MSPC fate decision through PGE2 release, providing insights into the precise and highly regulated communication between matrix- bound bone cells and BM- MSPCs, which dictates bone formation and remodeling.