Limits...
Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development.

Bassett JH, van der Spek A, Logan JG, Gogakos A, Bagchi-Chakraborty J, Murphy E, van Zeijl C, Down J, Croucher PI, Boyde A, Boelen A, Williams GR - Endocrinology (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH

Related in: MedlinePlus

X-ray microradiography. A, Gray scale and pseudocolored images of femurs from P42 WT and GPB5KO mice. The gray scale pixel distribution was stretched between 0 and 256 levels relative to polyester, aluminum, and steel standards. Gray scale images were divided into 16 equal intervals, each represented by a different color to aid visual presentation of digital images. In these pseudocolored images, low mineral content is green and high mineral content pink. B, Relative frequency histograms of bone mineralization densities in which the gray scale pixel distribution is shown in relation to each of the 16 equally sized color bins (n = 4–6 per genotype, each gender). Kolmogorov-Smirnov test, GPB5KO vs WT; **, P < .01; ***, P < .001. Scale bar, 1000 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4541616&req=5

Figure 3: X-ray microradiography. A, Gray scale and pseudocolored images of femurs from P42 WT and GPB5KO mice. The gray scale pixel distribution was stretched between 0 and 256 levels relative to polyester, aluminum, and steel standards. Gray scale images were divided into 16 equal intervals, each represented by a different color to aid visual presentation of digital images. In these pseudocolored images, low mineral content is green and high mineral content pink. B, Relative frequency histograms of bone mineralization densities in which the gray scale pixel distribution is shown in relation to each of the 16 equally sized color bins (n = 4–6 per genotype, each gender). Kolmogorov-Smirnov test, GPB5KO vs WT; **, P < .01; ***, P < .001. Scale bar, 1000 μm.

Mentions: Digital x-ray microradiography demonstrated increased BMC in juvenile GPB5KO mice compared with WT, and this difference was greater in males than females (Figure 3). Micro-CT and qBSE-SEM analyses were performed to determine whether the increased BMC was a consequence of increased bone volume, increased bone mineralization, or both.


Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development.

Bassett JH, van der Spek A, Logan JG, Gogakos A, Bagchi-Chakraborty J, Murphy E, van Zeijl C, Down J, Croucher PI, Boyde A, Boelen A, Williams GR - Endocrinology (2015)

X-ray microradiography. A, Gray scale and pseudocolored images of femurs from P42 WT and GPB5KO mice. The gray scale pixel distribution was stretched between 0 and 256 levels relative to polyester, aluminum, and steel standards. Gray scale images were divided into 16 equal intervals, each represented by a different color to aid visual presentation of digital images. In these pseudocolored images, low mineral content is green and high mineral content pink. B, Relative frequency histograms of bone mineralization densities in which the gray scale pixel distribution is shown in relation to each of the 16 equally sized color bins (n = 4–6 per genotype, each gender). Kolmogorov-Smirnov test, GPB5KO vs WT; **, P < .01; ***, P < .001. Scale bar, 1000 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4541616&req=5

Figure 3: X-ray microradiography. A, Gray scale and pseudocolored images of femurs from P42 WT and GPB5KO mice. The gray scale pixel distribution was stretched between 0 and 256 levels relative to polyester, aluminum, and steel standards. Gray scale images were divided into 16 equal intervals, each represented by a different color to aid visual presentation of digital images. In these pseudocolored images, low mineral content is green and high mineral content pink. B, Relative frequency histograms of bone mineralization densities in which the gray scale pixel distribution is shown in relation to each of the 16 equally sized color bins (n = 4–6 per genotype, each gender). Kolmogorov-Smirnov test, GPB5KO vs WT; **, P < .01; ***, P < .001. Scale bar, 1000 μm.
Mentions: Digital x-ray microradiography demonstrated increased BMC in juvenile GPB5KO mice compared with WT, and this difference was greater in males than females (Figure 3). Micro-CT and qBSE-SEM analyses were performed to determine whether the increased BMC was a consequence of increased bone volume, increased bone mineralization, or both.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus