Advanced science (Weinheim, Baden-Wurttemberg, Germany)Sep 28, 2023

Key Role of the Piezo1/β-catenin/ATF4 Pathway in Maintaining Stem Cell Properties of Gli1+ Bone Marrow Cells During Bone Loss Caused by Simulated Weightlessness

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 16, 2026

Abstract

Bone marrow-derived stem cells show a significant downregulation of Piezo1 expression during disuse osteoporosis.

Disuse osteoporosis results in decreased bone mass due to abnormal mechanical stimulation.
In a model simulating microgravity, bone marrow-derived stem cells are identified as the most affected cell cluster.
Systemic activation of Piezo1 through yoda1 appears to mimic mechanical stimulation effects and reduce bone loss.
Activation of Piezo1 promotes proliferation and differentiation of specific stem cells by enhancing signaling pathways.
Inhibiting key signaling pathways reduces the positive effects of Piezo1 activation on bone loss.
Piezo1 activation may also provide slight benefits in alleviating osteoporosis in older mice.

Simplified

Disuse osteoporosis is characterized by decreased bone mass caused by abnormal mechanical stimulation of bone. Piezo1 is a major mechanosensitive ion channel in bone homeostasis. However, whether intervening in the action of Piezo1 can rescue disuse osteoporosis remains unresolved. In this study, a commonly-used hindlimb-unloading model is employed to simulate microgravity. By single-cell RNA sequencing, bone marrow-derived mesenchymal stem cells (BMSCs) are the most downregulated cell cluster, and coincidentally, Piezo1 expression is mostly enriched in those cells, and is substantially downregulated by unloading. Importantly, activation of Piezo1 by systemically-introducing yoda1 mimics the effects of mechanical stimulation and thus ameliorates bone loss under simulated microgravity. Mechanistically, Piezo1 activation promotes the proliferation and osteogenic differentiation of Gli1BMSCs by activating the β-catenin and its target gene activating transcription factor 4 (ATF4). Inhibiting β-catenin expression substantially attenuates the effect of yoda1 on bone loss, possibly due to inhibited proliferation and osteogenic differentiation capability of Gli1BMSCs mediated by ATF4. Lastly, Piezo1 activation also slightly alleviates the osteoporosis of OVX and aged mice. In conclusion, impaired function of Piezo1 in BMSCs leads to insufficient bone formation especially caused by abnormal mechanical stimuli, and is thus a potential therapeutic target for osteoporosis. + +

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Key Role of the Piezo1/β-catenin/ATF4 Pathway in Maintaining Stem Cell Properties of Gli1+ Bone Marrow Cells During Bone Loss Caused by Simulated Weightlessness

Abstract

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