The pivotal role of the Hes1/Piezo1 pathway in the pathophysiology of glucocorticoid-induced osteoporosis
Nagahiro Ochiai, Yuki Etani, Takaaki Noguchi, Taihei Miura, Takuya Kurihara, Yuji Fukuda, Hidetoshi Hamada, Keisuke Uemura, Kazuma Takashima, Masashi Tamaki, Teruya Ishibashi, Shohei Ito, Satoshi Yamakawa, Takashi Kanamoto, Seiji Okada, Ken Nakata, Kosuke Ebina
Nagahiro Ochiai, Yuki Etani, Takaaki Noguchi, Taihei Miura, Takuya Kurihara, Yuji Fukuda, Hidetoshi Hamada, Keisuke Uemura, Kazuma Takashima, Masashi Tamaki, Teruya Ishibashi, Shohei Ito, Satoshi Yamakawa, Takashi Kanamoto, Seiji Okada, Ken Nakata, Kosuke Ebina
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Research Article Bone biology Therapeutics

The pivotal role of the Hes1/Piezo1 pathway in the pathophysiology of glucocorticoid-induced osteoporosis

Abstract

Glucocorticoid-induced osteoporosis (GIOP) lacks fully effective treatments. This study investigated the role of Piezo1, a mechanosensitive ion channel component 1, in GIOP. We found reduced Piezo1 expression in cortical bone osteocytes from patients with GIOP and a GIOP mouse model. Yoda1, a Piezo1 agonist, enhanced the mechanical stress response and bone mass and strength, which were diminished by dexamethasone (DEX) administration in GIOP mice. RNA-seq revealed that Yoda1 elevated Piezo1 expression by activating the key transcription factor Hes1, followed by enhanced CaM kinase II and Akt phosphorylation in osteocytes. This improved the lacuno-canalicular network and reduced sclerostin production and the receptor activator of NF-κB/osteoprotegerin ratio, which were mitigated by DEX. Comparative analysis of mouse models and human GIOP cortical bone revealed downregulation of mechanostimulated osteogenic factors, such as osteocrin, and cartilage differentiation markers in osteoprogenitor cells. In human periosteum-derived cells, DEX suppressed differentiation into osteoblasts, but Yoda1 rescued this effect. Our findings suggest that reduced Piezo1 expression and activity in osteocytes and periosteal cells contribute to GIOP, and Yoda1 may offer a novel therapeutic approach by restoring mechanosensitivity.

Authors

Nagahiro Ochiai, Yuki Etani, Takaaki Noguchi, Taihei Miura, Takuya Kurihara, Yuji Fukuda, Hidetoshi Hamada, Keisuke Uemura, Kazuma Takashima, Masashi Tamaki, Teruya Ishibashi, Shohei Ito, Satoshi Yamakawa, Takashi Kanamoto, Seiji Okada, Ken Nakata, Kosuke Ebina

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Figure 6

Differential gene expression analysis in response to mechanical stress under DEX treatment and investigation of the Piezo1 transcription factor.

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Differential gene expression analysis in response to mechanical stress u...
(A) Mouse tibial gene expression profiling was performed following mechanical loading using RNA-seq. Subcutaneous injections of 1 mg/kg DEX (DEX group) or distilled water (Vehicle group) were administered 5 times over 7 days. The left tibia underwent mechanical stress (40 cycles of −13 N force for 0.1 seconds at 10-second intervals, 3 times weekly) using an ElectroForce 5500 system. The right tibia remained unloaded as a control. Tibiae were flash-frozen for RNA extraction and sequencing 4 hours after final loading on day 5. (B and C) Differentially expressed genes (DEGs) are presented for the vehicle (B) and DEX (C) groups upon loading. Statistical significance was determined using the DESeq2 Wald test, highlighted with red dots for adjusted P values of less than 0.05. (D) Comparisons between vehicle- and DEX-treated groups under loading conditions revealed changes in genes such as Piezo1 (log2 fold change [log2FC] = −0.38, adjusted P value [Padj] = 3.0 × 10–3), Tnfsf11b (log2FC = −0.48, Padj = 7.0 × 10–4), and Tnfrsf11a (log2FC = 0.67, Padj = 1.8 × 10–2). (E) Gene Ontology (GO) overrepresentation analysis revealed impaired response to mechanical stress under DEX, with terms ranked by gene ratio and the bone-related terms highlighted (adjusted for multiple comparisons using an FDR). (F) A Venn diagram integrates data on Piezo1 transcription factor candidates from the ChIP atlas and RNA-seq. (G) Gene expression changes upon mechanical stress (low-intensity pulsed ultrasound, LIPUS) in MLO-Y4 cells are depicted. Piezo1 transcription factor candidates (mapped from previous research by Shimizu et al., ref. 19; GEO GSE162674) are highlighted in red. Hes1, hairy and enhancer of split 1; Vdr, vitamin D receptor; Bhlhe41, basic helix-loop-helix family, member 41.