title: Chondrocyte-specific knockout of the G protein G(s)alpha leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation.
abstract: G(s)alpha is a ubiquitously expressed G protein alpha-subunit that couples receptors to adenylyl cyclase. Mice with chondrocyte-specific ablation of the G(s)alpha gene had severe epiphyseal and growth plate abnormalities and ectopic cartilage formation within the metaphyseal region of the tibia. These results show that G(s)alpha negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTH-rP receptor in growth plate chondrocytes.
  
  
  BACKGROUND
  G(s)alpha is a ubiquitously expressed G protein alpha-subunit that mediates signaling through G protein-coupled receptors to activate the cAMP/protein kinase A signaling pathway. Although studies suggest an important role for G(s)alpha in regulating growth plate development, direct in vivo results examining this role are lacking.
  
  
  METHODS
  The G(s)alpha gene was ablated in murine cartilage by mating mice with loxP sites surrounding the G(s)alpha promoter and first exon with collagen 2a1 promoter-Cre recombinase transgenic mice. Skeletal tissues were studied by gross and microscopic pathology, and gene expression was determined by in situ hybridization.
  
  
  CONCLUSIONS
  Mice with complete chondrocyte-specific G(s)alpha deficiency (homozygotes) died within minutes after birth and had severe epiphyseal and growth plate defects with shortening of the proliferative zone and accelerated hypertrophic differentiation of growth plate chondrocytes, a phenotype similar to that of PTH/PTH-related peptide (PTHrP) receptor knockout mice. Indian hedgehog and PTH/PTHrP receptor expression in prehypertrophic chondrocytes was unaffected in mutant mice. PTHrP expression in periarticular cartilage was increased in the mutant mice, probably because of the closer proximity of Ihh-secreting chondrocytes to the periarticular zone. In addition, these mice developed ectopic cartilage at the anterior side of the metaphyseal region in the tibia. Mice with partial G(s)alpha deficiency (heterozygotes) exhibited no phenotype. These results show that G(s)alpha negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTHrP receptor in epiphyseal and growth plate chondrocytes.
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Akio
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities; D002454:Cell Differentiation / Q000502:physiology; D019902:Chondrocytes / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000502:physiology*; D005804:Genes, Lethal; D006132:Growth Plate / Q000002:abnormalities* / Q000254:growth & development*; D053823:Hedgehog Proteins; D051379:Mice; D018345:Mice, Knockout; D044162:Parathyroid Hormone-Related Protein / Q000032:analysis / Q000378:metabolism; D010641:Phenotype; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; D015534:Trans-Activators; D019205:GTP-Binding Protein alpha Subunits, Gs