title: Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development.
abstract: The ancestral glycoprotein hormone thyrostimulin is a heterodimer of unique glycoprotein hormone subunit alpha (GPA)2 and glycoprotein hormone subunit beta (GPB)5 subunits with high affinity for the TSH receptor. Transgenic overexpression of GPB5 in mice results in cranial abnormalities, but the role of thyrostimulin in bone remains unknown. We hypothesized that thyrostimulin exerts paracrine actions in bone and determined: 1) GPA2 and GPB5 expression in osteoblasts and osteoclasts, 2) the skeletal consequences of thyrostimulin deficiency in GPB5 knockout (KO) mice, and 3) osteoblast and osteoclast responses to thyrostimulin treatment. Gpa2 and Gpb5 expression was identified in the newborn skeleton but declined rapidly thereafter. GPA2 and GPB5 mRNAs were also expressed in primary osteoblasts and osteoclasts at varying concentrations. Juvenile thyrostimulin-deficient mice had increased bone volume and mineralization as a result of increased osteoblastic bone formation. However, thyrostimulin failed to induce a canonical cAMP response or activate the noncanonical Akt, ERK, or mitogen-activated protein kinase (P38) signaling pathways in primary calvarial or bone marrow stromal cell-derived osteoblasts. Furthermore, thyrostimulin did not directly inhibit osteoblast proliferation, differentiation or mineralization in vitro. These studies identify thyrostimulin as a negative but indirect regulator of osteoblastic bone formation during skeletal development.
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: J H Duncan
authors.initials: JH
authors.lastname: Bassett
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: van der Spek
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: John G
authors.initials: JG
authors.lastname: Logan
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Gogakos
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Bagchi-Chakraborty
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Williams
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Elaine
authors.initials: E
authors.lastname: Murphy
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Clementine
authors.initials: C
authors.lastname: van Zeijl
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Down
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Croucher
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Boyde
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Anita
authors.initials: A
authors.lastname: Boelen
authors.affiliation: Molecular Endocrinology Laboratory (J.H.D.B., J.G.L., A.G., J.B.C., E.M., G.R.W.), Department of Medicine, Imperial College London, London, W12 0NN United Kingdom; Department of Endocrinology (A.v.d.S., C.v.Z., A.Boe.), Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, The Netherlands; Bone Biology Program (J.D., P.I.C.), Garvan Institute of Medical Research, Sydney, NSW 2010 Australia; and Centre for Oral Growth and Development (A.Boy.), Queen Mary, University of London, London, E1 4NS United Kingdom.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Williams
mesh_terms: D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism*; D016466:CHO Cells; D002113:Calcification, Physiologic; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis; D019899:Paracrine Communication; D010641:Phenotype; D011989:Receptors, Thyrotropin / Q000378:metabolism; D013972:Thyrotropin / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D011989:Receptors, Thyrotropin; C458339:thyrostimulin; D013972:Thyrotropin