Mechanosensory and mechanotransductive processes mediated by ion channels in articular chondrocytes: Potential therapeutic targets for osteoarthritis

Figures & data

Figure 1. Conceptual illustration of the cellular mechanotransduction mechanism mediated by ion channels in articular chondrocytes

Table 1. The mechanosensory and mechanotransductive process of articular chondrocytes mediated by ion channels

Study	Cell/Tissue	Ion channel and mechanical stimuli	Mechanosensory and mechanotransductive process and mechanoadaptation
Wu et al (2000)	Growth plate chondrocytes	SACs, L-type VGCCs, stretch-induced cartilage matrix deformation	Synthesis of matrix protein, chondrocyte proliferation and differentiation
Srinivasan et al. (2015)	T-type VGCC KO mice and WT mice, MC3T3-E1	T-type VGCCs, dynamic compression	Matrix protein, mechanically induced OA phenotype
Parisi et al. (2018)	Embryonic chick hindlimb explants of chick articular joint	SACs, L-type VGCCs, dynamic compression	Ca^2+ influx, mechanically induced cellular responses
Tanaka et al. (2005)	rat growth plate chondrocytes	Ca^2+ channels sensitive to nifedipine, mechanical strain	Parathyroid hormone-related protein, chondrocyte maturation and matrix formation
Yellowley et al. (2002)	BACs	SACs, membrane stretch	Ca^2+ influx, altered membrane potential
Chowdhury et al (2006)	BACs	Purinergic 2 receptor ion channels, SACs, dynamic compression	ATP release, Ca^2+ influx, inhibition of NO-induced catabolic effect on articular cartilage
Millward-Sadler et al (2004)	Normal human chondrocytes	P2Y2 purinergic receptor, SK channels, mechanical stimulation at 0.33 Hz for 20 minutes	ATP release, membrane hyperpolarization
Lee et al. (2000)	Normal human articular chondrocytes	SK channels, SACs, 0.33 Hz cyclical pressure-induced strain	Phosphorylation of p125, p90, and p70, FAK, β-catenin and integrin
Mouw et al. (2007)	BACs	K^+ channels, Ca^2+ channels, SACs, static or dynamic compression	Ca^2+ signaling pathways, synthesis of glycosaminoglycan and matrix protein
Sánchez et al(2003)	BACs	SACs, VAHCs, membrane stretch	Na^+ influx, H^+ efflux, membrane depolarization
Sanchez, et al(2011)	Human articular chondrocytes	BKCa channels, membrane stretch	K^+ efflux, membrane, hyperpolarization, matrix turnover
Sanchez et al (2010)	Articular chondrocytes from healthy human and OA patients	BKCa channels, SACs, membrane stretch	K^+ efflux, Na^+ influx, altered membrane potential
Hdud et al. (2014)	Equine articular chondrocytes	TRPV4, BKCa channels, membrane stretch	ERK1/2 and p38 MAPK protein phosphorylation, altered expression of TRPV4 and BKCa channels
Sanchez et al. 2011	Human articular chondrocytes	BKCa channels, membrane stretch	K^+ efflux, membrane hyperpolarization
Lee et al. (2014)	Chondrocytes of femoral condyles from skeletally mature female pigs	Piezo1/2, cell strain in smooth lateral expanded cells under vertical compression(injurious level of strain)	Ca^2+ influx, altered membrane potential, maladaptive chondrocyte responses, cartilage degeneration
O’Conor et al. (2014)	Articular cartilage chondrocytes from the femur and ulnas of skeletally immature pigs	TRPV4, dynamic compressive loading	Ca^2+ influx, enhanced articular cartilage matrix synthesis and mechanical property
Zelenski et al. (2015)	Murine articular chondrocytes	TRPV4, hypotonic stress	Ca^2+ influx and Ca^2+ signaling pathways
Somogyi et al. (2015)	Chicken and murine articular chondrocytes	TRPV3 receptor, uniaxial cyclic compressive force	Increased expression of TRPV3 receptor, matrix synthesis
Kobayakawa et al. (2016)	HCS-2/8 cells, a human chondrocyte line	TRPV4, cyclic tensile strain	Activation of TRPV4, up-regulation of ADAM10-regulation of CD44 cleavage
Servin-Vences et al. (2017)	Primary chondrocytes from mice, HEK-293 cells	TRPV4, Piezo1, substrate-deflection, membrane stretch	Ca^2+ influx, mechanical transduction of substrate-deflection and membrane stretch
Lv, M, et al. (2018)	Murine articular chondrocytes	TRPV4, T-type VGCCs, SACs, ECM deformation and membrane strain induced by compression	Intracellular Ca^2+ oscillation
Yang et al. (2018)	Human articular chondrocytes from OA patients	Piezo1, cyclic stretch	Up-regulation of piezo1 protein
Karamesinis et al. (2017)	ATDC5 cell line derived from mouse teratocarcinoma cells	TRPP1,TRPP2, continuous hydrostatic pressure	Up-regulation of TRPP1 and TRPP2, regulation of chondrocyte differentiation
Du et al. (2020)	Primary chondrocytes from mice	TRPV4, piezo2, cyclic tensile strain	Ca^2+ influx, altered membrane potential
Liu et al. (2013)	MSCs	SACs, mechanical stimulation applied on cultured MSCs by silicon nanowire	Ras/Raf/MEK/ERK signaling cascades, adhesion, chondrocyte proliferation, and differentiation of MSCs
Shimazaki, A., et al. (2006)	Human normal and OA articular chondrocytes	NMDA receptor(ligand-gated ion channels),mechanical stimuli at 0.33 Hz	Membrane hyperpolarization
Mouw, J. K et al. (2007)	BACs	Ca^2+ channels, ATP-dependent Ca^2+ pumps, dynamic compression	Synthesis of protein and sulfated glycosaminoglycan
Xu, B et al. (2019)	Rat articular chondrocyte	TRPV4, membrane stretch	Ca^2+ influx
Valhmu, W. B et al. (2002)	BACs	CRACs, compressive stress of 0.1 MPa for 1 h	Compression-induced ACAN mRNA

Table 2. Articular chondrocytes in response to hind limb unloading or simulated microgravity

Study	Cell/Tissue	Decreased mechanical stimulation	Results
Wuest et al. (2018)	BACs	TRPV4, simulated microgravity induced by RPM	Altered expression of TRPV4, preserved chondrocyte phenotype
Basso et al(2006)	Articular and growth plate cartilage	Hind limb	Increased expression of iNOS, impaired articular cartilage, deteriorated joint biomechanics
Nomura et al. (2017)	Male C57BL/6 J mice	Hind limb, joint immobilization	Altered ALP and aggercanase activity, decreased ACAN content subchondral bone atrophy, cartilage degeneration

Table 3. The role of ion channels in osteoarthritis

Study	Cell/Tissue	Ion channel and intenvention	Results
Funabashi et al. (2010)	OUMS-27 cell line	SK channels, CRAC channels, histamine	K^+ efflux through SK channels, increased intracellular Ca^2+ concentration via nonselective cation channels including CRAC channels, membrane hyperpolarization
Li et al. (2017)	Human chondrocytes from OA patients	Piezo1, GsMTx4, a PIEZO-blocking peptide	Suppressed expression of apoptosis-related genes
Sooampon et al. (2013)	Human periodontal ligament (HPDL) cells, human osteoblasts	Piezo1, GsMTx4	Ca^2+ influx, attenuated deteriorated response of chondrocytes to injurious mechanical strain
O’Conor et al. (2016)	Conditional knockout (cKO) mice	Gene knock down of TRPV4 channel	Decreased total periarticular bone volume, reduced severity of aging-associated OA
Ogawa et al. (2019)	The ATDC5 cell line	TRPV4, GSK1016790A, a selective TRPV4 agonist	Activation of TRPV4-ICAM-1-up-regulation of chondrogenic marker genes including SOX9 and ACAN, HA facilitated TRPV4-induced chondrogenesis
Srinivasan et al. (2015)	KO and WT mice	Gene knock down of T-type VGCCs	Enhanced cartilage degeneration and subchondral bone resorption
Kuduk, S. D., et al. (2010), Izumi, M., et al. (2012)	KO and WT mice, rat osteoarthritis models	Gene knock down of ASIC-3, the ASIC3 inhibitor A-317,567, ASIC3 selective peptide blocker (APETx2)	Altered expression of ASIC3 in knee joint afferents, reversed osteoarthritis pain and mechanical hyperalgesia
Schuelert, N., et al. (2010)	Rat osteoarthritis models	The cannabinoid CB2 receptor agonist GW405833	Reduced mechanosensitivity of afferent nerve fibers in control joints, nociceptive responses in OA joints
Shimazaki, A., et al. (2006)	Human normal and OA articular chondrocytes	NMDA receptor(ligand-gated ion channels), CaMKII inhibitor	Inhibited membrane potential, upregulation of aggrecan mRNA
Clark et al. (2010)	KO mice	Gene knock down of TRPV4	Severe OA degeneration
Lee et al. (2014)	Murine chondrocytes	Piezo1, GsMTx4, siRNA	Attenuated maladaptive chondrocyte responses
Zelenski et al. (2015)	Murine articular chondrocytes	Gene knock down of TRPV4	Suppressed mechanically induced Ca^2+ influx and formation of pericellular matrix
Moilanen, L. J., et al. (2015)	Murine articular chondrocytes	Pharmacological blockade and gene knock down of TRPA1	Suppressed iodoacetate-induced OA
O’Conor, C. J., et al. (2016)	cKO mice	Gene knock down of TRPV4	Reduced severity of aging-associated OA
He, B. H., et al. (2017)	OA mice	Mechanosensitive ion channels, the selective inhibitor GsMTx4	Reduced activation of dorsal horn nociceptive circuits and primary mechanical allodynia
Xing, R., et al. (2017)	OA mice	TRPA1, TRPV4	Upregulation of TRPA1 and TRPV4 mechanical hyperalgesia induced by OA
Parisi, C., et al. (2018)	Chick joint	Pharmacological blockade of SACs, VGCCs,	Removed effects of mechanical stimulation on joint cartilage growth and shape development
Raouf, R., et al. (2018)	Rat DRG nerons	Piezo2, overexpression and gene knock down of annexin A6	Attenuated mechanical hyperalgesis induced by OA
Richter, F., et al. (2019)	Rat DRG nerons	TRPV4, agonist 4αPDD, GSK 1016790 A and antagonist RN-1734	Altered mechanonociception of the normal and inflamed joint
Xu, B., et al. (2019)	Rat articular chondrocytes	Pharmacological blockade and gene knock down of TRPV4	Attenuated cartilage degeneration in rat OA anterior cruciate-ligament transection (ALCT) models
Nummenmaa, E., et al. (2020)	Rat articular chondrocytes, human OA chondrocytes	Pharmacological blockade and gene knock down of TRPA1	Downregulation of the pro-inflammatory cytokine interleukin-6 (IL-6), IL-6 family cytokines leukemia inhibitory factor (LIF) and IL-11
Fu, S., et al. (2021)	Rat articular chondrocytes	Pharmacological blockade or activation of TRPV4	Pro-inflammatory signaling and cartilage degradation