scholarly journals EphrinB2/EphB4 inhibition in the osteoblast lineage modifies the anabolic response to parathyroid hormone

2013 ◽  
Vol 28 (4) ◽  
pp. 912-925 ◽  
Author(s):  
Farzin M Takyar ◽  
Stephen Tonna ◽  
Patricia WM Ho ◽  
Blessing Crimeen-Irwin ◽  
Emma K Baker ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Anabolic Response ◽  
Osteoblast Lineage

scholarly journals Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy

2015 ◽  
Vol 291 (4) ◽  
pp. 1631-1642 ◽  
Author(s):  
Partha Sinha ◽  
Piia Aarnisalo ◽  
Rhiannon Chubb ◽  
Ingrid J. Poulton ◽  
Jun Guo ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Phospholipase C ◽  
Osteoblast Differentiation ◽  
Bone Volume ◽  
Trabecular Bone Volume ◽  
Male And Female ◽  
Osteoblast Lineage

Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including Gsα. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsα in the osteoblast lineage. Postnatal removal of Gsα in the osteoblast lineage (P-GsαOsxKO mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1–34) (80 μg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-GsαOsxKO mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-GsαOsxKO mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via Gsα but not phospholipase C via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsα in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsα and Gq/11 act downstream of PTH on osteoblast differentiation.

scholarly journals Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43

2006 ◽  
Vol 119 (20) ◽  
pp. 4187-4198 ◽  
Author(s):  
D. J. Chung ◽  
C. H. M. Castro ◽  
M. Watkins ◽  
J. P. Stains ◽  
M. Y. Chung ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Bone Mass ◽  
Peak Bone Mass ◽  
Anabolic Response ◽  
Specific Deletion

Impaired bone anabolic response to parathyroid hormone in Fgf2−/− and Fgf2+/− mice

2006 ◽  
Vol 341 (4) ◽  
pp. 989-994 ◽  
Author(s):  
M.M. Hurley ◽  
Y. Okada ◽  
L. Xiao ◽  
Y. Tanaka ◽  
M. Ito ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Anabolic Response

scholarly journals SAT-392 The Role of β-arrestin2 in Bone Catabolic Response to Hyperparathyroidism In Vivo

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Gilberto Li Feng ◽  
Marc Grynpas ◽  
Jane Mitchell
Keyword(s):  
Parathyroid Hormone ◽  
Trabecular Bone ◽  
Histological Analysis ◽  
Bone Microarchitecture ◽  
Biomechanical Testing ◽  
Micro Computed Tomography ◽  
Anabolic Response ◽  
Protein Levels ◽  
Dynamic Histomorphometry

Abstract Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by elevated parathyroid hormone (PTH) levels and hypercalcemia caused by the overactive parathyroid glands, resulting in negative impacts on the skeleton including bone loss and increased bone fragility1. PTH binds and activates parathyroid hormone type 1 receptor (PTH1R) which primary couples to Gαs, stimulating the downstream effectors that mediate bone remodeling processes2. PTH1R activity is regulated by arrestins, specially β-arrestin2 (β-arr2), through signal termination and receptor internalization2. Previously, we have seen anabolic effects of hyperparathyroidism (cPTH) on trabecular bone in mice overexpressing Gαs3. We hypothesized that increased Gαs protein levels in osteoblasts outcompete β-arr binding to PTH1R, leading to reduced signal termination and increased bone formation. To test this hypothesis, we are testing if the deletion of β-arr2 will also result in an anabolic response to cPTH in this study. The response of β-arr2 knockout (KO) mice to cPTH have yet to be documented. The hypothesis of this study is that β-arr2 KO mice treated with cPTH will exhibit anabolic effects on the trabecular bone. Nine-week-old wild-type (WT) C57BL/6 and β-arr2 KO mice were treated for 14 days with either rPTH1-34 (80ng/g/day) or saline (PBS) using micro-osmotic pumps to simulate hyperparathyroidism. There are 8 groups (n=10 per group) including both sexes, 2 genotypes (WT and KO), and 2 treatment groups (PTH and PBS). Two 30 mg/kg doses of 0.6% calcein green were administered subcutaneously to mice at 7 and 2 days prior to euthanasia to label bones. Decalcified tibiae were embedded in paraffin for histological analysis. Undecalcified tibiae were embedded in plastic for dynamic histomorphometry. Micro-computed tomography (μCT) was used to access bone microarchitecture of femurs and vertebrae followed by biomechanical testing of bone strength. The μCT data of distal femurs show that cPTH treatment increased bone volume in female KO mice (6.864 ± 2.318 vs 4.690 ± 1.555 %; P= 0.0328; n=9 per group) and maintained bone in male KO mice (13.37 ± 2.860 vs 13.38 ± 3.135; P= 0.9968, n= 10) compared to control. Histological analysis show higher osteoclastic activity in both sexes and genotypes when treated with cPTH, suggesting that the anabolic response may be at the level of osteoblasts and osteocytes. These promising results support our hypothesis that arrestin-mediated PTH receptor downregulation plays an importance role in bone weakness associated with hyperparathyroidism. These studies are important for understanding the clinical phenotype of PHPT patients and suggest that inhibition of β-arr2 in PHPT could be a path for drug therapy. References: (1) Mosekilde L. Clin Endocrinol 2008;69:1-9. (2) Ferrari SL et al., J Biol Chem 1999; 274:29968–29975 (3) Zhang L. PhD thesis University of Toronto, 2018.

scholarly journals Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone?

2010 ◽  
Vol 285 (36) ◽  
pp. 28164-28173 ◽  
Author(s):  
Dominique D. Pierroz ◽  
Nicolas Bonnet ◽  
Paul A. Baldock ◽  
Michael S. Ominsky ◽  
Marina Stolina ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Anabolic Response
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