Article thumbnail

Gs G Protein–Coupled Receptor Signaling in Osteoblasts Elicits Age-Dependent Effects on Bone Formation

By Edward C Hsiao, Benjamin M Boudignon, Bernard P Halloran, Robert A Nissenson and Bruce R Conklin


Age-dependent changes in skeletal growth are important for regulating skeletal expansion and determining peak bone mass. However, how G protein–coupled receptors (GPCRs) regulate these changes is poorly understood. Previously, we described a mouse model expressing Rs1, an engineered receptor with high basal Gs activity. Rs1 expression in osteoblasts induced a dramatic age-dependent increase in trabecular bone with features resembling fibrous dysplasia. To further investigate how activation of the Gs-GPCR pathway affects bone formation at different ages, we used the tetracycline-inducible system in the ColI(2.3)+/Rs1+ mouse model to control the timing of Rs1 expression. We found that the Rs1 phenotype developed rapidly between postnatal days 4 and 6, that delayed Rs1 expression resulted in attenuation of the Rs1 phenotype, and that the Rs1-induced bone growth and deformities were markedly reversed when Rs1 expression was suppressed in adult mice. These findings suggest a distinct window of increased osteoblast responsiveness to Gs signaling during the early postnatal period. In addition, adult bones encode information about their normal shape and structure independently from mechanisms regulating bone expansion. Finally, our model provides a powerful tool for investigating the effects of continuous Gs-GPCR signaling on dynamic bone growth and remodeling. © 2010 American Society for Bone and Mineral Research

Topics: Original Article
Publisher: Wiley Subscription Services, Inc., A Wiley Company
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (1997). A G protein–linked receptor for parathyroid hormone and parathyroid hormone–related peptide.
  2. (2003). A schoolbased exercise intervention elicits substantial bone health benefits: a 2-year randomized controlled trial in girls. Pediatrics.
  3. Age and fracture healing: a statistical analysis of 418 cases of tibial shaft fractures.
  4. (1997). Age-related decreases in stimulatory G protein–coupled adenylate cyclase activity in osteoblastic cells.
  5. (2005). Aging increases stromal/osteoblastic cell-induced osteoclastogenesis and alters the osteoclast precursor pool in the mouse. J Bone Miner Res.
  6. and old rats have similar changes in mRNA expression of many skeletal genes after fracture despite delayed healing with age.
  7. Cellular basis for age-related changes in fracture repair.
  8. Changes in the skeletal cell proliferative response to trauma concomitant with aging.
  9. (1993). Characterization of beta-adrenergic receptors on rat and human osteoblast-like cells and demonstration that beta-receptor agonists can stimulate bone resorption in organ culture. Bone Miner.
  10. Clinical phenotypes and molecular genetic mechanisms of Carney complex.
  11. (2001). Col1a1-driven transgenic markers of osteoblast lineage progression. J Bone Miner Res.
  12. (2006). Collins MT.Spectrumandnaturalhistory of fibrousdysplasiaofbone. J Bone Miner Res.
  13. (1999). Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice. Nat Biotechnol.
  14. Conditional expression of a Gicoupled receptor in osteoblasts results in trabecular osteopenia.
  15. Continuous activation of GaQ in osteoblasts results in osteopenia through impaired osteoblast differentiation.
  16. Deficiency of the G protein alpha-subunit G(s)a in osteoblasts leads to differential effects on trabecular and cortical bone.
  17. (2006). Developmental origins of osteoporotic fracture. Osteoporos Int.
  18. Developmental regulation of the growth plate.
  19. Engineered G protein–coupled receptors reveal independent regulation of internalization, desensitization and acute signaling.
  20. (2008). Engineering GPCR signaling pathways with RASSLs. Nat Methods.
  21. EnsrudKE, etal. Oneyear ofalendronateafter one year of parathyroid hormone (1–84) for osteoporosis.
  22. (2008). Evaluations of organ system development in juvenile toxicology testing. Reprod Toxicol.
  23. (2007). Exercise when young provides lifelong benefits to bone structure
  24. (1997). Expression of mRNAs for neuropeptide receptors and beta-adrenergic receptors in human osteoblasts and human osteogenic sarcoma cells. Neurosci Lett.
  25. Fibrous dysplasia of bone in the McCune-Albright syndrome: abnormalities in bone formation.
  26. (2006). Formation: Maturation and Functional Activities of Osteoblast Lineage Cells. In:
  27. (2002). Foundation. America’s Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation. Washington: National Osteoporosis Foundation;
  28. (1993). G protein mutations in human disease. Clin Biochem.
  29. GNAS: normal and abnormal functions.
  30. (2008). Growth and bone development. Nestle Nutr Workshop Ser Pediatr Program.
  31. (1981). Healing of femoral neck fractures: influence of fracture reduction and age. Ann Chir Gynaecol.
  32. (2006). Hypermethylation of CpGs in the promoter of the COL1A1 gene in the aged periodontal ligament. J Dent Res.
  33. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.
  34. (2007). Modifying ligand-induced and constitutive signaling of the human 5-HT4 receptor. PLoS One.
  35. (2002). Mouse a1(I)-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast. Dev Dyn.
  36. Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass.
  37. (2004). PTH differentially regulates expression of RANKL
  38. (1996). PTH/PTHrP receptor in early development and Indianhedgehog-regulatedbonegrowth.Science.
  39. Receptor activator of nuclear factor kB ligand (RANKL)/osteoprotegerin (OPG) ratio is increased in severe osteolysis.
  40. Reproduction of human fibrous dysplasia of bone in immunocompromised mice by transplanted mosaics of normal and Gsa-mutated skeletal progenitor cells.
  41. (1988). Skak SV,Jensen TT.Femoralshaft fracturein 265children: log-normal correlation with age of speed of healing. Acta Orthop Scand.
  42. (2003). Species comparison of postnatal bone growth and development. Birth Defects Res B Dev Reprod Toxicol.
  43. (2004). The importance of bisphosphonate therapy in maintaining bone mass in men after therapy with teriparatide [human parathyroid hormone(1–34)]. Osteoporos Int.
  44. The receptors for mammalian sweet and umami taste.
  45. The role of prostaglandin E receptor subtypes (EP1, EP2, EP3, and EP4) in bone resorption: an analysis using specific agonistsfor the respectiveEPs.
  46. TSH is a negative regulator of skeletal remodeling.
  47. (2000). Uncovering molecular mechanisms involved in activation of G protein–coupled receptors. Endocr Rev.
  48. Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling in osteoblasts.