Osteocyte connexin hemichannels and prostaglandin E 2 release dictate bone marrow mesenchymal stromal cell commitment.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 Δ130 to 136 (inhibiting both hemichannels and gap junctions). BM-MSPCs from Δ130 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 Δ130 to 136 mice. Conversely, R76W, with more functional hemichannels, exhibited effects similar to WT mice or even greater opposite effects than Δ130 to 136 mice. Prostaglandin E 2 (PGE 2 ), released from active Cx43 hemichannels, inhibited adipogenesis and promoted osteogenesis via the PGE 2 receptor EP4 and ERK1/2 signaling. Inhibition of Cx43 hemichannels or EP4 led to increased adipogenic-biased MSPCs. Moreover, administration of a C

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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