FIGURE 4.

Proposed mechanotransduction pathways in osteocytes for therapeutic targets showing intracellular signaling in response to the mechanical stimulation. (A) Pulsatile fluid flow triggered sphingolipid signaling to regulate the lipid mediators such as sphingosine-1-phosphate (S1P) production that upregulates the intracellular calcium ions (Ca²⁺) levels and prostaglandin E2 (PGE₂) synthesis/release in osteocytes. (B) Fluid shear stress upregulates suppressor of mothers against decapentaplegic 2/3 (Smad2/3) phosphorylation triggering transforming growth factor-beta (TGF-β) signaling, resulting in sclerostin (SOST) downregulation. This is independent of TGF-β receptor-induced response. (C) Wnt/β-catenin signaling can be elicited by direct response to extracellular matrix deformation via integrins or fluid shear stress, which is important to maintain osteocyte viability and anabolic effect by accumulating Taz and β-catenin (β-cat). Interestingly, both TGF-β and Wnt/β signaling may interact with each other to induce bone formation, however, the exact mechanism is not clear. (D) Under mechanical stimuli, adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling governs energy homeostasis in osteocytes by increasing the AMP/adenosine triphosphate (ATP) ratio for inhibiting apoptosis and decrease receptor activator of nuclear factor-κB ligand (RANKL) expression. (E) Forkhead box O (FoxO) signaling is activated to protect osteocytes from oxidative stress and mitochondria damage caused by aging and reduced mechanical stimulation. Without FoxO activation, osteocytes lead to senescence and apoptosis. (F) Parathyroid hormone receptor (PTHr) is activated both by mechanical stimulation as well as parathyroid hormone. This receptor upregulates histone deacetylase 5 (HDAC5), which inhibits myocyte enhancer factor 2 (MEF2C), responsible for negative Wnt signaling molecules, SOST and dickkopf-related protein 1 (DKK1). Figure created using BioRender.