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The pivotal role of the Hes1–Piezo1 pathway in the pathophysiology of glucocorticoid-induced osteoporosis [human_GIOP]

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 sequencing 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 lacuno-canalicular network and reduced sclerostin production and receptor activator of nuclear factor kappa beta/osteoprotegerin ratio, which were mitigated by DEX. Comparative analysis of mouse models and human GIOP cortical bone revealed downregulation of mechano-stimulated osteogenic factors, such as osteocrin, and cartilage differentiation markers in osteoprogenitor cells. In human periosteal-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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276529 | GEO | 2024/12/18

REPOSITORIES: GEO

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

Project description: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 sequencing 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 lacuno-canalicular network and reduced sclerostin production and receptor activator of nuclear factor kappa beta/osteoprotegerin ratio, which were mitigated by DEX. Comparative analysis of mouse models and human GIOP cortical bone revealed downregulation of mechano-stimulated osteogenic factors, such as osteocrin, and cartilage differentiation markers in osteoprogenitor cells. In human periosteal-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.

2024-12-18 | GSE276391 | GEO

Expression Data from ATDC5 cells treated with Yoda1

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Piezo1 channels restrain ILC2s and regulate the development of airway hyperactivity [piezo1KO]

Project description:Mechanosensitive ion channels sense force and pressure in immune cells to drive the inflammatory response in highly mechanical organs. Here we report that Piezo1 channels repress group 2 innate lymphoid cells (ILC2s)-driven type 2 inflammation in the lungs. Piezo1 is induced on lung ILC2s upon activation, as genetic ablation of Piezo1 in ILC2s increases their function and exacerbates the development of airway hyperreactivity (AHR). Conversely, Piezo1 agonist Yoda1 reduces ILC2-driven lung inflammation. Mechanistically, Yoda1 inhibits ILC2 cytokine secretion and proliferation in a KLF2-dependent manner, as we further found that Piezo1 engagement reduces ILC2 oxidative metabolism. Consequently, in vivo Yoda1 treatment notably reduces the development of AHR in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s express and induce Piezo1 upon activation, as Yoda1 treatment of humanized mice reduces human ILC2-driven AHR. Our studies define Piezo1 as a critical regulator of ILC2s and we propose the potential of Piezo1 activation as a novel therapeutic approach for the treatment of ILC2-driven allergic asthma.

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Role of PTH on Gene Expression in Osteocytes of Cortical Long Bone from Mature Mice

Project description:Femur and Tibia of Mice 3 months of age were dissected, growth plate removed, and serial digested with collagenase-trypsin to remove endosteal and periosteal cells. The cortical bone tubes, highly enriched in osteocye in their natural bone matrix environment where then cultured with and and with out PTH at 250nM for 24hr, RNA extracted and biotinylated cDNA prepared, and hybrized to Illumina MouseWG-6_V2 arrays. Data was analyzed using Genome Studio-Gene Expression Module from Illumina. The design was to explore gene expression in osteocytes as they reside in their bone matrix with normal lacunar-canalicular structure, and the role of parathyroid hormone (PTH) on changes in gene expression due to hormone treatment.

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Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin [RNA-Seq]

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Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin [ChIP-Seq]

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