Bone tissue regeneration: role of osteocyte mechanosensing and mechanotransduction

Critical-sized bone defects caused by trauma, tumor resection, injury, and/or surgical intervention are posing significant clinical challenges. Bone tissue regeneration is crucial for restoring critical-sized bone defects. Central to the bone regenerative capability is the dynamic interplay between bone cells, particularly osteocytes, which are the most abundant and long-lived bone cells, functioning as key mechanosensors in bone. Osteocytes detect mechanical stimuli, for example, fluid shear stress, compressive or tensile strain, and hydrostatic pressure, and convert these into biochemical signals through mechanotransduction. The biochemical signals (eg, calcium ions, Wnt, etc.) regulate osteoblast and osteoclast-mediated remodeling. Osteocytes communicate with osteoblasts and osteoclasts via paracrine factors, including nitric oxide, prostaglandins, and sclerostin. Moreover, estrogen deficiency is known to alter osteocyte mechanosensitivity, impair osteocyte signaling, and dysregulate bone remodeling. Understanding how mechanical and hormonal factors affect osteocyte signaling is essential for developing effective therapeutic interventions. This concise review explores the role of osteocyte mechanosensing and mechanotransduction in bone tissue regeneration to improve bone healing, especially in critical-sized bone defects. The cellular and molecular mechanisms underlying bone regeneration and remodeling are discussed, including the role of stem cells in bone regeneration, that is, osteogenic differentiation potential and secretion of bioactive factors that promote new bone formation and vascularization. Finally, we explore the translational and clinical implications of osteocyte mechanobiology, discussing current challenges and potential advancements in bone tissue engineering and regenerative medicine. By integrating fundamental mechanobiological principles with clinical strategies, this concise review highlights the clinical potential of modulating osteocyte behavior for improved bone regeneration.