Table 2.
The functions and mechanisms of GPCR in osteoblasts and osteocytes
| 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 | Adipogenic signaling | Promotes adipogenesis over osteoblast differentiation 50. |
| A2AR (ADORA2A) | Rhodopsin family - α subgroup (Adenosine) | Adenosine | Gαs | cAMP/PKA | Stimulates osteoblast activity and suppresses osteoclast activity; promotes bone regeneration 50, 52. |
| A3AR (ADORA3) | Rhodopsin family - α subgroup (Adenosine) | Adenosine | Gαi | Anti-inflammatory signaling | Reduces inflammatory cytokines (e.g., TNF-α); promotes bone repair in inflammatory conditions 53. |
| ADORA2B | Rhodopsin family - α subgroup (Adenosine) | Adenosine | Gαs | cAMP/PKA | Inhibits adipogenesis and stimulates osteoblast differentiation 51. |
| ADRA1A (α1-AR) | Rhodopsin family - α subgroup (Adrenergic) | Epinephrine, Norepinephrine, Phentolamine | Gαq | / | Negatively regulates Bmp4 expression by up-regulating Nfil3/E4BP4 in osteoblasts 41. |
| ADRA2A (α2A-AR) | Rhodopsin family - α subgroup (Adrenergic) | Epinephrine, Norepinephrine, Phentolamine | Gαi | Neuro-endocrine signaling | SNP rs553668 and rs1800544 locate in gene; alters mRNA stability and BMD 42. |
| ADRB1 | Rhodopsin family - α subgroup (Adrenergic) | Norepinephrine, isoproterenol | Gαs | cAMP/PKA | Inhibits disuse-induced bone loss by reducing osteocyte apoptosis 37. |
| ADRB2 | Rhodopsin family - α subgroup (Adrenergic) | Norepinephrine, Isoproterenol, Epinephrine | Gαs | cAMP/PKA → RANKL upregulation | Deficiency increases bone mass 38-40. |
| CaSR | Glutamate family | Extracellular Ca²⁺ | Gαq/Gαi | mTORC2/AKT-β-catenin, NF-κB/JAK-Stat3 | Promotes bone formation (via β-catenin); drives pathological bone formation in inflammatory states 34. |
| CNR2 (CB2) | Rhodopsin family - α subgroup (Cannabinoid) | Endocannabinoids, CB2 agonists | Gαi | Osteoclast survival suppression | Agonists promote osteoblast differentiation and protect against ovariectomy-induced bone loss 55, 56. |
| EP2 | Rhodopsin family | PGE2 | Gαs | cAMP/PKA | Enhances osteoblast differentiation and mineralization 49. |
| GABABR | Glutamate family | GABA | Gαi | cAMP suppression → BMP2/RANKL downregulation | Inhibits osteoblastogenesis; knockout increases BMP2 expression but reduces BMD 45. |
| GPR161 | Other 7TM receptors | / | Gαi (putative) | Sonic Hedgehog (Shh) pathway suppression | Inhibits intramembranous bone formation; knockout completely blocks osteoblastogenesis 29, 46. |
| GPR39 | Other 7TM receptors | Zinc | Gαq | Unknown (matrix deposition regulation) | Knockout causes disordered matrix deposition (low collagen, high mineral content) 36. |
| GPR48 (LGR4) | Adhesion family | R-spondin | Gαs | cAMP-PKA-Atf4 | Regulates embryonic osteoblast differentiation and mineralization; knockout delays bone formation 31. |
| GPRC6A | Glutamate family | Calcium/Amino acids | Gαq | ERK activation | Suppresses osteoblast differentiation and ALP activity; knockout reduces bone formation 16. |
| GRM1 (mGluR1) | Glutamate family | Glutamate | Gαq | / | Knockout causes premature growth plate fusion and osteoblast dysfunction 48. |
| LGR5 (GPR49) | Adhesion family | R-spondin | Gαs | Wnt/β-catenin activation | Promotes osteoblast differentiation and bone formation 30. |
| LPAR1 (EDG2/GPCR26) | Rhodopsin family - δ subgroup (Lipids) | Lysophosphatidic acid (LPA) | Gα12/13 | RANKL→MAPK/AKT-NF-κB | Knockout reduces bone mineralization, increases osteocyte apoptosis, and bone porosity 47. |
| PTH1R | Secretin family | PTH/ PTHrP | Gαs | cAMP/PKA | Activation (e.g., by teriparatide) stimulates bone formation; key therapeutic target for osteoporosis 6, 7. |
| XCR1 | Other 7TM receptors | XCL1 | Gαi (putative) | / | Promotes osteoblast differentiation and enhances bone formation 54. |