Mechanosignaling in Osteoporosis: When Cells Feel the Force

Abstract

Bone is a highly mechanosensitive tissue, where mechanical signaling plays a central role in maintaining skeletal homeostasis. Mechanotransduction regulates the balance between bone formation and resorption through coordinated interactions among bone cells. Key mechanosensing structures-including the extracellular/pericellular matrix (ECM/PCM), integrins, ion channels, connexins, and primary cilia, translate mechanical cues into biochemical signals that drive bone adaptation. Disruptions in mechanotransduction are increasingly recognized as an important factor in osteoporosis. Under pathological conditions, impaired mechanical signaling reduces bone formation and accelerates bone resorption, leading to skeletal fragility. Defects in mechanotransduction disrupt key pathways involved in bone metabolism, further exacerbating bone loss. Therefore, targeting mechanotransduction presents a promising pharmacological strategy for osteoporosis treatment. Recent advances have focused on developing drugs that enhance bone mechanosensitivity by modulating key mechanotransduction pathways, including integrins, ion channels, connexins, and Wnt signaling. A deeper understanding of mechanosignaling mechanisms may pave the way for novel therapeutic approaches aimed at restoring bone mass, mechanical integrity, and mechanosensitive bone adaptation.

Keywords: mechanosensitive ion channels; mechanosignaling; mechanotransduction; osteoporosis; secondary osteoporosis.

Figure 1

Mechanosensing and signal transduction in bone cells. Osteocytes, as the primary mechanosensitive cells in bone, respond to mechanical stimuli by secretion of signaling molecules such as RANKL, OPG, SOST, IGF-1, PGE2, and CXCL5. Through various signaling pathways, including but not limited to Wnt/β-catenin, YAP/TAZ, and RANKL, they influence the differentiation and function of osteoblasts and osteoclasts. Similarly, osteoblasts and osteoclasts, as well as their progenitors, can also sense mechanical stimuli and regulate the bone remodeling process. Standard arrows indicate stimulatory effects, thin-tailed arrows represent translocation or transport of substances, blocked lines denote inhibitory effects, and dashed arrows signify weakened or reduced effects. Ca²⁺: calcium ion, CaM: calmodulin, CaMKII: calcium/calmodulin-dependent protein kinase II, CSF-1R: colony-stimulating factor 1 receptor, CXCL5: C-X-C motif chemokine ligand 5, CXCR1/2: C-X-C motif chemokine receptor 1/2, EP2/4: prostaglandin E2 receptor 2/4, F-actin: filamentous actin, IGF-1: insulin-like growth factor 1, IGF-1R: insulin-like growth factor 1 receptor, LRP: low-density-lipoprotein receptor-related protein, MAPK: mitogen-activated protein kinase, M-CSF: macrophage colony-stimulating factor, MSC: mesenchymal stem cell, mTOR: mechanistic target of rapamycin, NF-κB: nuclear factor kappa-B, NFATc1: nuclear factor of activated T cells cytoplasmic 1, OPG: osteoprotegerin, PGE2: prostaglandin E2, PIEZO1: Piezo-type mechanosensitive ion channel component 1, PTH-1R: parathyroid hormone 1 receptor, RANK: receptor activator of nuclear factor kappa-Β, RANKL: receptor activator of nuclear factor kappa-Β ligand, SOST: sclerostin, TAZ: transcriptional coactivator with PDZ-binding motif, TRPV4: transient receptor potential vanilloid 4, YAP: Yes-associated protein.

Figure 2

Mechanosensitive structures and their downstream pathways in the bone remodeling process. Mechanical stimuli are transmitted through the extracellular and pericellular matrix, sensed by primary cilia, ion channels, integrins, or connexons, and translated into biological signals through signaling cascades to modulate osteogenic and osteoclastogenic gene expression. Additionally, agents targeting specific mechanoreceptors are shown (pink), which can enhance osteogenic effects. Standard arrows indicate stimulatory effects, thin-tailed arrows represent translocation or transport of substances, blocked lines denote inhibitory effects, and dashed arrows signify weakened or reduced effects. A2BAR: A2B adenosine receptor, AC6: adenylyl cyclase 6, ACP5: acid phosphatase 5, AKT: protein kinase B, ATP: adenosine triphosphate, Ca²⁺: calcium ion, CaM: calmodulin, CaMKII: calcium/calmodulin-dependent protein kinase II, cAMP: cyclic adenosine monophosphate, cGMP: cyclic guanosine monophosphate, CREB: cAMP response element binding protein, Cx43: connexin 43, Cx43-M2: Cx43 hemichannel agonist, EP2/4: prostaglandin E2 receptor 2/4, ERK: extracellular signal-regulated kinase, FAK: focal adhesion kinase, FOS: proto-oncogene c-Fos, Gli: GLI family zinc finger protein, GPR161: G-protein-coupled receptor 161, GSK: GSK1016790A (TRPV4 agonist), HDAC6: histone deacetylase 6, MAPK: mitogen-activated protein kinase, mTOR: mechanistic target of rapamycin, NFATc1: nuclear factor of activated T cells 1, NF-κB: nuclear factor kappa-B, NICD: Notch intracellular domain, NO: nitric oxide, NOTCH3: Notch receptor 3, OPG: osteoprotegerin, OPN: osteopontin, OSX: osterix, PGE2: prostaglandin E2, PI3K: phosphoinositide 3-kinase, PIEZO1: Piezo-type mechanosensitive ion channel component 1, PKA: protein kinase A, PKC: protein kinase C, PKG: protein kinase G, RANK: receptor activator of nuclear factor kappa-B, RANKL: receptor activator of nuclear factor kappa-B ligand, RhoA: Ras homolog family member A, ROCK: Rho-associated protein kinase, RUNX2: Runt-related transcription factor 2, sGC: soluble guanylyl cyclase, Smo: Smoothened, TAZ: transcriptional co-activator with PDZ-binding motif, TRAF6: TNF receptor-associated factor 6, TRPV4: transient receptor potential cation channel subfamily V member 4, YAP: Yes-associated protein, Yoda1: PIEZO1 agonist.

Figure 3

Etiologies of osteoporosis.