Table 1.

List of known mechanosensors in chondrocytes and their potential downstream genes and pathways

Mechanosensors in chondrocytes	Types of mechanical stimulation	Potential downstream molecules or pathways	Relationship with OA and cartilage health	Reference
TRPV4	N/A	N/A	The absence of TRPV4 resulted in osteoarthritic changes, particularly in male mice, suggesting a chondroprotective role for TRPV4 that is possibly mediated by its Ca2+ gating in response to hypotonicity.	25
	Mechanical (10% cyclic tensile strain (CTS), 0.33 Hz, 24 h) or osmotic loading (200, 315 or 400 mOsm, referred as hypo-, iso- or hyperosmotic, 24 h)	Inhibiting NO, PGE2, and inflammation through regulating HDAC6	Mechanical, osmotic, or pharmaceutical activation of TRPV4 regulates the HDAC6-dependent modulation of ciliary tubulin and is an anti-inflammatory factor in chondrocytes.	26
	Anterior cruciate-ligament transection (ALCT)	Activation of TRPV4 increases Ca2+ influx to trigger apoptosis by increasing FAS-associated protein with death domain and cleaved caspase-3, -6, -7, and -8 levels.	TRPV4 is upregulated in ALCT-induced OA articular cartilage, and administration of a TRPV4 inhibitor attenuates cartilage degeneration.	121
	Dynamic compressive load (a 10% peak-to-peak sinusoidal strain (7% offset) at 1 Hz for 3 h·d−1); hypo-osmotic treatments (400 → 200 mOsm and 600 → 400 mOsm, respectively)	Upregulated gene expression of TGFβ3, COL2a1, ACAN as well as increases in total GAG and collagen; downregulated ADAMTS5 and NOS2	TRPV4-dependent intracellular Ca2+ signaling has been detected in agarose-embedded chondrocytes. Inhibition of TRPV4 during dynamic loading prevents mechanically mediated regulation of proanabolic and anticatabolic genes.	19
	Natural aging; destabilization of the medial meniscus (DMM)	N/A	Loss of TRPV4-mediated cartilage mechanotransduction in adulthood reduces the severity of aging-associated OA. However, loss of chondrocyte TRPV4 does not prevent OA development following the destabilization of the medial meniscus (DMM).	122
	Viscoelasticity of alginate hydrogels mimic environment with different mechanical stress	TRPV4 controls the phosphorylation of GSK3β, which has been associated with changes in anabolic gene expression	The TRPV4-GSK3β molecular axis is disrupted in osteoarthritic chondrocytes; therefore OA cells cannot sense or respond to altered viscoelasticity of the surrounding matrix. Restoring chondrocyte ability may help slow the progression of OA.	27
Piezo1/2	Chondrocytes are probed via atomic force microscopy. Cartilage explants are injured with a 3 mm stainless steel punch that penetrates cartilage and reaches to bone	Ca2+ flux triggers chondrocyte apoptosis	High strain leads to Ca2+ flux into chondrocytes via PIEZO channels; and inhibiting Piezos with the peptide GsMTx4 protects articular chondrocytes from mechanically induced cell death.	28
	Cyclic stretching for 0 h/2 h/12 h/24 h/48 h at a 20% amplitude and a period of 10 times per minute	Upregulation of Piezo1 results in highly expressed Kif18A and β-tubulin, leading to chondrocyte cell cycle arrest and inhibits chondrocyte proliferation	Piezo1-siRNA reduces the inhibition of chondrocyte proliferation induced by mechanical stretch by downregulating the expression of Kif18A and inhibiting the depolymerization of microtubules.	123
	Static compressive loading for 0, 2, 12, 24, and 48 h	Activation of the MAPK/ERK1/2 signaling pathway	Piezo1 causes the apoptosis of the human chondrocyte by activating the classic MAPK/ERK1/2 signal pathway.	32
	High-speed pressure clamp and elastomeric pillar arrays	N/A	Both TRPV4 and PIEZO1 channels contribute to currents triggered by stimulation applied at cell–substrate contacts, but only PIEZO1 mediates stretching-activated currents in chondrocytes.	29
	AFM probe (flat, tipless) compresses single cells cyclically with a trigger force of 300–500 nN every 10 s for 2 min)	Piezo1 induction of excess intracellular Ca2+ at baseline, with elevated resting state Ca2+ in turn rarefying the F-actin cytoskeleton and amplifies mechanically induced deformation-based microtrauma	Increased Piezo1 expression in chondrocytes results in a feed-forward pathomechanism whereby the increased activity of Piezo1 induces excess intracellular Ca2+ at baseline and accelerates OA progression.	30
Primary cilium	Cyclic loading strain at 5%, 1 Hz on primary human chondrocytes	Primary cilia induction of ERK1/2 and CITED2 expression, leading to suppressed expression of MMP-1 and -13	Primary cilia sense moderate cyclic loading to inhibit the expression of MMPs and thus slow OA progression.	36
	N/A	Upregulation of Hedgehog (Hh) signaling (Ptch1 and Gli1), leading to overexpressed Mmp1, ADAMST5, ColX, Runx2	Deletion of IFT (intraflagellar transport) 88 can prevent primary cilium assembly in cartilage, which leads to acquisition of an OA phenotype characterized by reduced stiffness and increased expression levels of OA markers, including MMP-13, Adamts5, ColX, and Runx2 levels	124
	Indentation strain: A plane-ended impermeable cylinder (178 µm diameter) is applied to tissue with a tare load of 0.05 g and held for 200 s. Further indentation force is applied in increments of 5 µm with 200 s relaxation time between each application	N/A	Loss of primary cilia causes a significant reduction in the mechanical properties of cartilage, particularly in the deeper zones and possibly the underlying bone. This loss confirms the importance of primary cilia in the development of mechanically functional articular cartilage.	125
	N/A	Lack of primary cilia leading to reduced hedgehog (Hh) signaling and increased Wnt signaling	Loss of IFT80 and primary cilia block chondrocyte differentiation by disrupting ciliogenesis and altering Hh- and Wnt-mediated signal transduction, which in turn alters articular cartilage formation.	126
	Cyclic tensile strain (CTS; 0.33 Hz, 10% or 20% strain)	Hedgehog signaling	Mechanical loading activates primary cilium-mediated hedgehog signaling and ADAMTS-5 expression in adult articular chondrocytes, but this response is lost at high strain due to HDAC6-mediated cilia disassembly.	33
Integrin	N/A	Activate inflammatory and degradative mediators through Fyn, FAK	Activates αVβ3 signaling in many articular cell types and contributes to inflammation and joint destruction in OA.	39
	Knee joints are stressed either by forced exercise (moderate mechanical load) or by partial resection of meniscus followed by forced exercise (high mechanical load)	Lack of α5β1-Fibronectin binding induction of matrix-degrading enzymes, MMP3, MMP13	OA induced by meniscectomy followed by forced exercise accelerates cartilage degradation in α5β1 integrin-depleted mice.	127
	Pressure-induced strain (PIS) at a frequency of 0.33 Hz (2 s on/1 s off) for 20 min	Integrin-dependent signaling pathway leading to the opening of SK (small conductance Ca2+-dependent K+ channels) and membrane hyperpolarization by IL-4	Integrin-regulated production of IL-4 confers protection to chondrocytes by inhibiting cartilage degradation and promoting matrix synthesis in normal articular cartilage.	44
Pericellular matrix	Hypotonic (165 mOsm, ionic strength (IS) = 0.075 M), isotonic (330 mOsm, IS = 0.15 M), and hypertonic (550 mOsm, IS = 0.23 M) stress	Decorin, a small leucine-rich proteoglycan, is a key determinant of cartilage pericellular matrix micromechanics, with defective decorin exhibiting decreased intracellular calcium activity under both physiological and osmotically treated fluid environmental conditions in situ	Decorin is an essential constituent of the native cartilage matrix, and pericellular matrix of decorin-null murine cartilage leads to reduced content of aggrecan, the major chondroitin sulfate proteoglycan in cartilage, and a mild increase in collagen II-based fibril diameter, as well as a significant reduction in the cartilage micromodulus, suggesting that modulating decorin activities may enhance cartilage regeneration.	128
	Isotonic (300 mOsm) or hypotonic (200 mOsm) stress	Col6a1-knockout in PCM increases TRPV4-mediated calcium signaling and cell swelling	Alterations in PCM properties in OA or aging can influence mechanotransduction via TRPV4 or other ion channels, thereby influencing cartilage health.	50
Cytoskeleton	Continuous hydrostatic pressure (24 MPa) for 3 h	Actin and tubulin composed of cytoskeletal influence the number of cell organelles	Pressure induced OA-like distribution of actin and tubulin and a reduction in the number of cell organelles involved in the synthesis of collagen and proteoglycans.	129
	Homogeneous isotropic compression/stretch of 10% strain	N/A	Cytoskeletal Vimentin-disrupted chondrocytes showed a lower fluidization–resolidification response rate and reduced cellular stiffness.	130
	Continuous, uniaxial, and unconfined compressive load (0.5 MPa, Hz) for 10 and 30 min	Reduction in F-actin polymerization, resulting in increased expression of catabolic mediators (MMPs)	Thymosin β4, a putative mechanically regulated gene that inhibits F-actin polymerization results in increased expression of catabolic mediators (MMPs), leading to increased cartilage catabolism.	131
Nucleoskeleton	Hyperosmotic conditions (>400 mOsm·kg−1), hypo-osmotic conditions (100 mOsm·kg−1)	Nuclear morphology change induces chromatin condensation and decondensation, lead to altered gene expression	Alterations in chromatin structure are thought to influence gene expression and thereby regulate chondrocyte activity in response to mechanical stimulation, while the relation with OA needs further investigation.	56
	15% shear strain	Disruption of the nuclear envelope associated with lamin A/C depletion significantly increases nuclear strain in regions with low DNA concentration	Disruption to the nucleoskeleton induces an ellipsoidal morphology in nuclei and drives chondrocyte phenotype switching to fibroblast-like cells under load strain stimulation.	57
Mitochondria	Destabilization of the medial meniscus (DMM) induces abnormal loading in chondrocytes of knee cartilage	Mitochondrial superoxide, Sod2	Mechanical overload inhibits mitochondrial superoxide generation and Sod2 in cartilage, and its maintains continuous and accelerated mitochondrial oxidative damage in chondrocytes.	65
	A single impact load (a 500 gm weight dropped from a height of 50 mm)	Loading induces calcium release from the endoplasmic reticulum, causing mitochondrial membrane polarization and then activates caspase 9 to induce cell death.	Mitochondrial membrane depolarization via calcium quenching reduces the rate of impact-induced chondrocyte death.	132

The relationship between mechanosensors and OA is shown

TRPV4 transient receptor potential channel subfamily V member 4, NO nitric oxide, PGE2 prostaglandin e2, HDAC6 histone deacetylase 6, TGF-β transforming growth factor-beta, COL2 type II collagen, ACAN aggrecan, GAG glycosaminoglycan, ADAMT a disintegrin and metalloproteinase with thrombospondin motifs, NOS2 nitric oxide synthase, OA osteoarthritis, GSK-3β glycogen synthase kinase 3beta, GsMTX4 selective Piezo-inhibiting peptide, MAPK mitogen-activated protein kinase, ERK extracellular signal-regulated kinase, AFM atomic force microscopy, CITED2 E/D-rich carboxy-terminal domain-2, MMP matrix metalloproteinase, Hh signaling Hedgehog signaling, COLX type X collagen, RUNX2 Runt-related transcription Factor 2, IFT80/88 intraflagellar transport 80/88, FAK focal adhesion kinase, PCM pericellular matrix, F-actin filamentous actin, Sod2 superoxide dismutase 2, and NA not available