Table 4.
The functions and mechanisms of GPCR in chondrocytes
| GPCR Name | GRAFS Classification | Ligand | Coupled G Protein Subtype | Signaling Pathway | Functional/Phenotypic Changes and references |
|---|---|---|---|---|---|
| A2AR | Rhodopsin family - α subgroup (Adenosine) | Adenosine | Gαs | FoxO/autophagy activation | Stimulation improves cartilage function; enhances autophagy and reduces inflammation 114. |
| A3AR (ADORA3) | Rhodopsin family - α subgroup (Adenosine) | Adenosine | Gαi | Suppression of RUNX2/CaMKII | Agonists inhibit matrix degradation and cartilage hypertrophy in OA 108. |
| ADORA2B | Rhodopsin family - α subgroup (Adenosine) | Adenosine | Gαs | cAMP/PKA | Activation inhibits chondrogenic differentiation in MSCs by downregulating SOX9 and COL2A1 50. |
| ADRA1A (α1-AR) | Rhodopsin family - α subgroup (Adrenergic) | Epinephrine, Norepinephrine, Phentolamine | Gαq | ERK/PKA | Low-dose NE induces apoptosis via α1-AR; accelerates OA pathogenesis 113. |
| ADRA2A (α2A-AR) | Rhodopsin family - α subgroup (Adrenergic) | Epinephrine, Norepinephrine, Phentolamine | Gαi | ERK1/2-PKA/cGMP | Activation ↑ MMPs and RANKL, causing cartilage degeneration; antagonists as enhancers of chondrogenesis and suppressors of hypertrophy, agonists induced detrimental hypertrophy 111. |
| ADRB2 (β-AR) | Rhodopsin family - α subgroup (Adrenergic) | Norepinephrine, Isoproterenol, Epinephrine | Gαs | ERK1/2-PKA/Jun-B | Agonists inhibit chondrocyte differentiation markers; high-dose NE reverses IL-1β damage 109, 110. |
| AT1R | Rhodopsin family | Angiotensin II | Gαq | ERK/PKA | High AT1R/AT2R ratio impedes chondrocyte proliferation under stress; inhibition promotes survival 115. |
| AT2R | Rhodopsin family | Angiotensin II | Gαi (putative) | Counteracts AT1R | Enhanced expression reduces apoptosis in stressed chondrocytes 115. |
| CaSR | Glutamate family | Extracellular Ca²⁺ | Gαq | Pro-differentiation signaling | Biomechanical stress ↑ CaSR expression, accelerating OA; calcilytics block cartilage degradation 15, 24, 33. |
| CNR1 (CB1) | Rhodopsin family - α subgroup (Cannabinoid) | Endocannabinoids, e.g., anandamide | Gαi | SIRT1 activation | Agonists protect against IL-1β-induced senescence and cell cycle arrest 117. |
| CNR2 (CB2) | Rhodopsin family - α subgroup (Cannabinoid) | Endocannabinoids, CB2 agonists | Gαi | Anti-inflammatory | Deficiency worsens OA; agonists reduce OA severity and enhance proteoglycan synthesis 117. |
| CCR2 | Rhodopsin family - γ subgroup (Chemokine) | CCL2 | Gαi | NF-κB/MAPK | Drives macrophage recruitment and cartilage erosion in OA; antagonism reduces synovitis and damage 93. |
| CCR5 | Rhodopsin family - γ subgroup (Chemokine) | CCL3/CCL4/CCL5 | Gαi | / | Deficiency protects against cartilage degeneration in OA 92. |
| CXCR2 | Rhodopsin family | CXCL1/CXCL8 | Gαi | AKT signaling | Maintains chondrocyte homeostasis; knockout increases osteoarthritis severity (↑ apoptosis, ↓ ECM) 90. |
| CXCR3 | Rhodopsin family | CXCL9/CXCL10/CXCL11 | Gαi | ER stress (CHOP/GRP78) | Elevated in OA; siRNA knockdown reduces nitrate-induced chondrocyte apoptosis 91. |
| CXCR4 | Rhodopsin family | CXCL12 | Gαi | SDF-1/CXCR4-Runx2 feedback loop | Promotes chondrocyte hypertrophy; blocking CXCR4 inhibits hypertrophy and delays growth plate closure 89. |
| EP1 | Rhodopsin family | PGE2 | Gαq | PGE2 signaling | Inhibits fracture healing; EP1 knockout accelerates bone repair 21. |
| EP2 | Rhodopsin family | PGE2 | Gαs | cAMP/PKA | Suppresses MMP-13 (anti-catabolic); combined EP2/EP4 activation mimics PGE2-induced collagen synthesis 100. |
| EP4 | Rhodopsin family | PGE2 | Gαs | cAMP/PKA | Cooperates with EP2 to regulate chondrocyte differentiation and matrix synthesis 21, 99. |
| GLP-1R | Secretin family | GLP-1 | Gαs | PI3K/Akt/NF-κB | Activation reduces ER stress, apoptosis, and inflammation; attenuates OA cartilage degeneration 132, 167. |
| GPR120 | Rhodopsin family - α subgroup (Fatty Acid) | Long-chain fatty acids | Gαq | SOX9-mediated ECM protection | Agonists rescue type II collagen and aggrecan expression; suppresses IL-1β-induced ECM loss 106. |
| GPBAR1 | Rhodopsin family | Bile acids | Gαs | Anti-senescence | Protects chondrocytes from IL-1β-induced senescence; activation reduces β-galactosidase activity 104. |
| GPR4 | Rhodopsin family | Protons | Gα12/13 or Gαq | NF-κB/MAPK | Drives OA progression; knockout or inhibition attenuates cartilage degradation 105. |
| GPR40 | Rhodopsin family | Medium/long-chain fatty acids | Gαq (putative) | NF-κB inhibition | Agonists reduce matrix-degrading enzymes and inflammation; slows OA progression 102. |
| GPR43 | Rhodopsin family | Short-chain fatty acids, e.g., propionate | Gαi | Anti-inflammatory signaling | Activated by butyrate; mitigates IL-1β-induced MMPs and collagen degradation 103. |
| GPR84 | Rhodopsin family | Medium-chain fatty acids | Gαi | NF-κB inhibition | Deficiency ↑ cartilage catabolism; activation blocks IL-1β-induced OA pathogenesis 107. |
| H4R (GPCR105) | Rhodopsin family - α subgroup (Histamine) | Histamine | Gαi | cAMP↓, MAPK↑ | Linked to hypertrophic chondrocyte differentiation (co-expressed with COLX) 98. |
| KOR (OPRK1) | Rhodopsin family | Dynorphin | Gαi | cAMP/CREB | Protects cartilage via ↑ anabolic enzymes and ↓ catabolism; agonists may treat early OA 101. |
| MC1R | Rhodopsin family - α subgroup (Melanocortin) | α-MSH | Gαs | cAMP/PKA | Reduces inflammatory cytokines and cartilage-degrading enzymes; enhances chondroprotective factors 97. |
| MC3R | Rhodopsin family - α subgroup (Melanocortin) | α-MSH | Gαs | cAMP/PKA | Synergizes with MC1R to suppress cartilage degradation in OA 97. |
| PAR2 | Rhodopsin family | Proteases, e.g., trypsin | Gαq | NF-κB/ERK | Promotes OA inflammation and cartilage damage; PAR2 antagonists reduce joint swelling and senescence 94-96. |