G-protein stimulatory subunit alpha and Gq/11α G-proteins are both required to maintain quiescent stem-like chondrocytes.
Round chondrocytes in the resting zone of the growth plate provide precursors for columnar chondrocytes and have stem-like properties. Here we demonstrate that these stem-like chondrocytes undergo apoptosis in the absence of the receptor (PPR) for parathyroid hormone-related protein. We examine the possible roles of heterotrimeric G-proteins activated by the PPR. Inactivation of the G-protein stimulatory α-subunit (G(s)α) leads to accelerated differentiation of columnar chondrocytes, as seen in the PPR knockout, but a remnant of growth cartilage remains, in contrast to disappearance of the growth cartilage in the PPR knockout. Stem-like chondrocytes lose their quiescence and proliferate upon G(s)α ablation. Inactivation of G(s)α in mice with a mutant PPR that cannot activate G proteins, Gq and G11, leads to a PPR knockout-like phenotype. Thus, G(s)α is the major mediator of the anti-differentiation action of the PPR, while activation of both G(s)α and Gq/11α is required for quiescence of stem-like chondrocytes.
1] Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden [2] Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114-2696, USA.
Andrei S
AS
Chagin
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden.
Karuna K
KK
Vuppalapati
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114-2696, USA.
Tatsuya
T
Kobayashi
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114-2696, USA.
Jun
J
Guo
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114-2696, USA.
Takao
T
Hirai
Metabolic Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1752, USA.
Min
M
Chen
Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
Stefan
S
Offermanns
Metabolic Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1752, USA.
Lee S
LS
Weinstein
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114-2696, USA.
Henry M
HM
Kronenberg
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism
D044385:GTP-Binding Protein alpha Subunits; D044168:Receptor, Parathyroid Hormone, Type 1; D043802:GTP-Binding Protein alpha Subunits, Gq-G11