scholarly journals PH domain and leucine rich repeat phosphatase 1 (Phlpp1) suppresses parathyroid hormone receptor 1 (Pth1r) expression and signaling during bone growth

2020 ◽  
Author(s):  
Samantha R. Weaver ◽  
Earnest L. Taylor ◽  
Elizabeth L. Zars ◽  
Katherine M. Arnold ◽  
Elizabeth W. Bradley ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Growth Plate ◽  
Endochondral Ossification ◽  
Bone Growth ◽  
Long Bone ◽  
Leucine Rich Repeat ◽  
Ph Domain ◽  
Mineral Density ◽  
Longitudinal Bone Growth ◽  
Deficient Mice

ABSTRACTEndochondral ossification is tightly controlled by a coordinated network of signaling cascades including parathyroid hormone (PTH). PH domain and leucine rich repeat phosphatase (Phlpp1) affects endochondral ossification by suppressing chondrocyte proliferation in the growth plate, longitudinal bone growth, and bone mineralization. As such, Phlpp1−/− mice have shorter long bones, thicker growth plates, and proportionally larger growth plate proliferative zones. The goal of this study was to determine how Phlpp1 deficiency affects PTH signaling during bone growth. Transcriptomic analysis revealed greater Pth1r expression and H3K27ac enrichment at the Pth1r promoter in Phlpp1-deficient chondrocytes. PTH(1-34) enhanced and PTH(7-34) attenuated cell proliferation, cAMP signaling, CREB phosphorylation, and cell metabolic activity in Phlpp1-inhibited chondrocytes. To understand the role of Pth1r action in the endochondral phenotypes of Phlpp1-deficient mice, Phlpp1−/− mice were injected with Pth1r ligand PTH(7-34) daily for the first four weeks of life. PTH(7-34) reversed the abnormal growth plate and long bone growth phenotypes of Phlpp1−/− mice but did not rescue deficits in bone mineral density or trabecular number. These results demonstrate that elevated Pth1r expression and signaling contributes to increased proliferation in Phlpp1−/− chondrocytes and shorter bones in Phlpp1-deficient mice. Our data reveal a novel molecular relationship between Phlpp1 and Pth1r in chondrocytes during growth plate development and longitudinal bone growth.

scholarly journals Exposure to the RXR Agonist SR11237 in Early Life Causes Disturbed Skeletal Morphogenesis in a Rat Model

2019 ◽  
Vol 20 (20) ◽  
pp. 5198
Author(s):  
Holly Dupuis ◽  
Michael Andrew Pest ◽  
Ermina Hadzic ◽  
Thin Xuan Vo ◽  
Daniel B. Hardy ◽  
...  
Keyword(s):  
Growth Plate ◽  
Endochondral Ossification ◽  
Bone Growth ◽  
Long Bone ◽  
Tunel Staining ◽  
Long Bones ◽  
Micro Computed Tomography ◽  
Calcified Tissue ◽  
Trap Staining ◽  
Stimulation Of

Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation in EO. Rats given SR11237 from post-natal day 5 to post-natal day 15 were harvested for micro-computed tomography (microCT) scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole-mount evaluation. RXR agonist-treated rats had shorter long bones than the controls and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape, in correspondence with p57 immunostaining. Additionally, SOX9-positive cells were found surrounding the calcified tissue. The epiphysis of SR11237-treated bones showed increased TRAP staining and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of the treated animals. This study suggests that stimulation of RXR causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models

scholarly journals Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth

2004 ◽  
Vol 180 (2) ◽  
pp. 247-255 ◽  
Author(s):  
J Wang ◽  
J Zhou ◽  
CM Cheng ◽  
JJ Kopchick ◽  
CA Bondy
Keyword(s):  
Growth Hormone ◽  
Growth Plate ◽  
Bone Growth ◽  
Long Bone ◽  
Null Mouse ◽  
Chondrocyte Proliferation ◽  
Chondrocyte Hypertrophy ◽  
Longitudinal Bone Growth ◽  
Germinal Zone ◽  
Igf I

The possibility that growth hormone (GH) has effects on long bone growth independent of insulin-like growth factor-I (IGF-I) has long been debated. If this is true, then long bone growth should be more profoundly affected by the absence of GH (since both GH and GH-stimulated IGF-I effects are absent) than by the absence of IGF-I alone (since GH is still present and actually elevated). To test this hypothesis, we compared long bone growth in mice with targeted deletions of Igf1 vs growth hormone receptor (Ghr). Tibial linear growth rate was reduced by approximately 35% in Igf1 null mice and by about 65% in Ghr null mice between postnatal days 20 and 40, a time of peak GH effect during normal longitudinal growth. The Igf1 null mouse growth plate demonstrated significant enlargement of the germinal zone; chondrocyte proliferation and numbers were normal but chondrocyte hypertrophy was significantly reduced. In contrast, the Ghr null mouse germinal zone was hypoplastic, chondrocyte proliferation and numbers were significantly reduced, and chondrocyte hypertrophy was also reduced. We have previously demonstrated that IGF-II is highly expressed in growth plate germinal and proliferative zones, so we considered the possibility that GH-stimulated IGF-II production might promote germinal zone expansion and maintain normal proliferation in the Igf1 null mouse growth plate. Supporting this view, IGF-II mRNA was increased in the Igf1 null mouse and decreased in the Ghr null mouse growth plate.Thus, in the complete absence of IGF-I but in the presence of elevated GH in the Igf1 null mouse, reduction in chondrocyte hypertrophy appears to be the major defect in longitudinal bone growth. In the complete absence of a GH effect in the Ghr null mouse, however, both chondrocyte generation and hypertrophy are compromised, leading to a compound deficit in long bone growth. These observations support dual roles for GH in promoting longitudinal bone growth: an IGF-I-independent role in growth plate chondrocyte generation and an IGF-I-dependent role in promoting chondrocyte hypertrophy. The question of whether GH has direct effects on chondrocyte generation is still not settled, however, since it now appears that IGF-II may medicate some of these effects on the growth plate.

scholarly journals Estrogen receptor specificity in the regulation of the skeleton in female mice

2001 ◽  
Vol 171 (2) ◽  
pp. 229-236 ◽  
Author(s):  
MK Lindberg ◽  
SL Alatalo ◽  
JM Halleen ◽  
S Mohan ◽  
JA Gustafsson ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Bone Growth ◽  
Fat Content ◽  
Mineral Density ◽  
Trabecular Bone Mineral Density ◽  
Longitudinal Bone Growth ◽  
Female Mice ◽  
Opposing Effects ◽  
Er Alpha

There are two known estrogen receptors, estrogen receptor-alpha (ER alpha) and estrogen receptor-beta (ER beta), which may mediate the actions of estrogen. The aim of the present study was to compare fat content, skeletal growth and adult bone metabolism in female mice lacking ER alpha (ERKO), ER beta (BERKO) or both ERs (DERKO). We demonstrate that endogenous estrogens decrease the fat content in female mice via ER alpha and not ER beta. Interestingly, the longitudinal bone growth was decreased in ERKO, increased in BERKO, but was intermediate in DERKO females, demonstrating that ER alpha and ER beta exert opposing effects in the regulation of longitudinal bone growth. The effects on longitudinal bone growth were correlated with similar effects on serum levels of IGF-I. A complex regulation of the trabecular bone mineral density (BMD), probably caused by a disturbed feedback regulation of estrogen and testosterone, was observed in female ER-inactivated mice. Nevertheless, a partial functional redundancy for ER alpha and ER beta in the maintenance of the trabecular BMD was observed in the female mice at 60 days of age. Thus, ER alpha and ER beta may have separate effects (regulation of fat), opposing effects (longitudinal bone growth) or partial redundant effects (trabecular BMD at 60 days of age), depending on which parameter is studied.

scholarly journals Exposure to the RXR agonist SR11237 in early life causes disturbed skeletal morphogenesis in a rat model

2019 ◽  
Author(s):  
Holly Dupuis ◽  
Michael Andrew Pest ◽  
Ermina Hadzic ◽  
Thin Xuan Vo ◽  
Daniel B. Hardy ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Long Bone ◽  
Tunel Staining ◽  
Long Bones ◽  
Micro Computed Tomography ◽  
Computed Tomography Scanning ◽  
Calcified Tissue ◽  
Trap Staining ◽  
Tomography Scanning

AbstractLongitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation on EO.Rats given SR11237 from post-natal day 5 to 15 were harvested for micro-computed tomography scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole mount evaluation.RXR agonist-treated rats were smaller than controls, and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape corresponding with P57 immunostaining. Additionally, SOX9 positive cells were found surrounding the calcified tissue. The epiphysis of SR11237 treated bones showed increased TRAP staining, and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of treated animals. Isolated mouse long bones treated with SR11237 grew significantly less than their DMSO controls.This study demonstrates that stimulation of the RXR receptor causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models.

Fluoride Inhibits Longitudinal Bone Growth by Acting Directly at the Growth Plate in Cultured Neonatal Rat Metatarsal Bones

2019 ◽  
Vol 197 (2) ◽  
pp. 522-532 ◽  
Author(s):  
Rui Ma ◽  
Shuang Liu ◽  
Tingting Qiao ◽  
Demin Li ◽  
Ruixue Zhang ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Neonatal Rat ◽  
Longitudinal Bone Growth ◽  
Metatarsal Bones
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