Pathway
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes
Osteocytes are mechanosensory cells in mineralized bone that have dendrites extending through lacunae (parallel with collagen fibers) and canaliculi (perpendicular to collagen fibers) to make contact with other osteocytes and with osteoblasts on the bone surface (reviewed in Moriishi and Komori 2022). Fluid flow and pressure in the lacunae and canaliculi are sensed by the dendrites and communicated to the cell body (inferred from mouse osteocytes in Burra et al. 2010), resulting in secretion of anabolic factors such as prostaglandin E2 (PGE2) that act to strengthen the bone (Siller-Jackson et al. 2008, Riquelme et al. 2021, reviewed in Zhao et al. 2023).
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Mechanosensitive PIEZO1 channels are opened by membrane stretch and transport calcium and sodium ions along their concentration gradients into the osteocyte. T-type voltage-sensitive calcium channels (CaV2 channles) open secondarily and augment the calcium influx. Cytosolic calcium activates Pannexin-1 (PANX1) channels, which transport ATP from the cytosol to the extracellular region. Extracellular ATP binds P2RX7 (P2X7) receptors located in a complex with PANX1. P2RX7 then transports cations including calcium into the cell and may act in an autocrine and paracrine manner to propagate waves of calcium influx.
Integrin alphaV:beta3 (ITGAV:ITGB3) located in the plasma membrane of dendrites binds the extracellular matrix of the lacunar or canicular wall. Fluid flow activates ITGAV:ITGB3 to phosphorylate AKT1 via a PI3K-dependent mechanism. Phospho-AKT1 then phosphorylates integrin alpha5 (ITGA5) and Connexin43 (GJA1) located in a complex in the plasma membrane of the cell body. Phospho-GJA1 transports ATP and PGE2 from the cytosol to the extracellular region (reviewed in Zhao et al. 2023).
CaV3.2 voltage-sensitive calcium channels also directly interact with the extracellular proteoglycan perlecan (PLN, PLC, HSPG2) and the alpha2delta1 subunit of the CaV3.2 complex (Reyes Fernandez et al. 2022). Physical force on perlecan may thus affect calcium transport by the CaV3.2 channels.
What the reference databases state
Statements
15 statements
15 statements · 1 reference database · Subject: Mechanical load activates signaling by PIEZO1 and integrins in osteocytes · Sources: Reactome
- AKT1 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- CACNA1H participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- CACNB1 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- CACNB2 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- CACNB3 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- GJA1 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- HSPG2 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- ITGA5 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- ITGAV participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- ITGB1 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- ITGB3 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- P2RX7 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
Show the remaining 3
- PANX1 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- PIEZO1 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only
- SPP1 participates in Mechanical load activates signaling by PIEZO1 and integrins in osteocytesProteinReactome R-HSA-9856532Inferred only