Table 3.
The functions and mechanisms of GPCR in osteoclasts
| GPCR Name | GRAFS Classification | Ligand | Coupled G Protein Subtype | Signaling Pathway | Functional/Phenotypic Changes and references |
|---|---|---|---|---|---|
| A1R (ADORA1) | Rhodopsin family - α subgroup (Amines) | Adenosine | Gαi | Pro-osteoclast signaling | Promotes osteoclast formation and bone loss 74. |
| A2AR (ADORA2A) | Rhodopsin family - α subgroup (Adenosine) | Adenosine | Gαs | cAMP/PKA | Inhibits osteoclast differentiation; agonists promote bone regeneration 74. |
| ADRB2 | Rhodopsin family - α subgroup (Adrenergic) | Norepinephrine, Isoproterenol, Epinephrine | Gαs | RANKL upregulation | Enhances osteoclastogenesis and bone resorption 38-40. |
| CaSR | Glutamate family | Extracellular Ca²⁺ | Gαq/Gαi | NF-κB, Akt | High Ca²⁺ inhibits osteoclast resorption; osteoblast knockout increases RANKL-driven resorption 67-71. |
| CNR1 (CB1) | Rhodopsin family - α subgroup (Cannabinoid) | Endocannabinoids, e.g., anandamide | Gαi | Apoptosis induction | Antagonists increase bone mass by promoting osteoclast apoptosis 78. |
| CNR2 (CB2) | Rhodopsin family - α subgroup (Cannabinoid) | Endocannabinoids, CB2 agonists | Gαi | Osteoclast survival suppression | Agonists promote osteoclast formation; antagonists inhibit bone loss 81. |
| DRD2 (D2DR) | Rhodopsin family - α subgroup (Dopamine) | Dopamine | Gαi | NF-κB suppression | Inhibits M1 macrophage polarization; restricts inflammatory osteolysis 82. |
| EBI2 (GPR183) | Rhodopsin family - γ subgroup (Chemokine) | 7α,25-OHC | Gαi | 7α,25-OHC → OCP migration/fusion | Promotes osteoclast precursor migration; defective signaling increases bone mass 58. |
| EP4 (PTGER4) | Rhodopsin family | PGE2 | Gαs | PGE2 → cytokine-driven resorption | Enhances osteoclast formation in inflammation; overexpression inhibits resorption 85-87. |
| F2r (Thrombin Receptor) | Rhodopsin family - δ subgroup (Thrombin) | Thrombin | Gαq/11 | Inhibiting Akt-GSK3β-NFATc1 and suppressing NF-κB signaling | Inhibits osteoclast formation and bone resorption 60. |
| GABABR | Glutamate family | GABA | Gαi | cAMP suppression → BMP2/RANKL downregulation | Knockout elevates ALP levels and BMP2/Osterix expression, which inhibits osteoclast formation by reducing RANKL production 45. |
| GPR120 (FFAR4) | Rhodopsin family - α subgroup (Fatty Acid) | Long-chain fatty acids | Gαq/Gαq11 | ROS suppression → antioxidant activation | Inhibits osteoclast formation/resorption; reduces ROS production 65. |
| GPR125 | Adhesion family | / | Gαq/12/13 (putative) | RANKL → MAPK/AKT-NF-κB | Promotes osteoclast differentiation/activation; knockdown reduces signaling 84. |
| GPR132 (G2A) | Other 7TM receptors | Lysophosphatidic acid, LPA | Gα12/13 | Macrophage polarization | Reduces M1-like macrophage infiltration; shifts to M2 polarization 64. |
| GPR30 | Other 7TM receptors | Estrogen | Gαi (putative) | Membrane estrogen signaling | Inhibits osteoclastogenesis via non-nuclear pathways 61. |
| GPR48 (LGR4) | Adhesion family | R-spondin | Gαs (putative) | cAMP-PKA-CREB → Atf4 | Delays embryonic osteoblast differentiation; postnatal knockout increases osteoclast activity 62, 63. |
| GPR54 | Other 7TM receptors | Kisspeptin | Gαq (putative) | Kp-10 → Dusp18/Src dephosphorylation | Suppresses osteoclast activity; prevents bone loss 66. |
| GPR55 | Other 7TM receptors | Lysophosphatidic acid, LPA | Gα12/13 (putative) | RANKL → NFATc1 activation | Enhances osteoclast maturation; inhibition reduces bone resorption 59. |
| GPRC6A | Glutamate family | Calcium/Amino acids | Gαq (putative) | ucOCN-mediated inhibition | Inhibits early osteoclast differentiation and resorption 72. |
| H4R (GPCR105) | Rhodopsin family - α subgroup (Histamine) | Histamine | Gαi (putative) | RANKL upregulation | Promotes RA-associated osteoclastogenesis; antagonists reduce bone destruction 88. |
| LPAR1 (EDG2/GPCR26) | Rhodopsin family - δ subgroup (Lipids) | Lysophosphatidic acid, LPA | Gα12/13 | RANKL → MAPK/AKT-NF-κB | Essential for osteoclast differentiation; antagonists inhibit resorption 83. |
| TAS1R3 | Glutamate family | Sweet tastants | Gαi (putative) | Nutrient sensing | Increases cortical bone mass; reduces osteoclast activity 73. |
| TSHR (LGR3) | Rhodopsin family - δ subgroup (Glycoprotein) | TSH | Gαs | TSH → cAMP/PKA | Inhibits osteoclastogenesis; knockout reduces bone strength 57. |