Inhibition of TGF-beta receptor signaling in osteoblasts leads to decreased bone remodeling and increased trabecular bone mass

Development ◽  
1999 ◽  
Vol 126 (19) ◽  
pp. 4267-4279 ◽  
Author(s):  
E. Filvaroff ◽  
A. Erlebacher ◽  
J. Ye ◽  
S.E. Gitelman ◽  
J. Lotz ◽  
...  
Keyword(s):  
Bone Formation ◽  
Transgenic Mice ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Bone Remodeling ◽  
Biomechanical Properties ◽  
Tgf Beta ◽  
Wild Type ◽  
Trabecular Bone Mass

Transforming growth factor-beta (TGF-beta) is abundant in bone matrix and has been shown to regulate the activity of osteoblasts and osteoclasts in vitro. To explore the role of endogenous TGF-(beta) in osteoblast function in vivo, we have inhibited osteoblastic responsiveness to TGF-beta in transgenic mice by expressing a cytoplasmically truncated type II TGF-beta receptor from the osteocalcin promoter. These transgenic mice develop an age-dependent increase in trabecular bone mass, which progresses up to the age of 6 months, due to an imbalance between bone formation and resorption during bone remodeling. Since the rate of osteoblastic bone formation was not altered, their increased trabecular bone mass is likely due to decreased bone resorption by osteoclasts. Accordingly, direct evidence of reduced osteoclast activity was found in transgenic mouse skulls, which had less cavitation and fewer mature osteoclasts relative to skulls of wild-type mice. These bone remodeling defects resulted in altered biomechanical properties. The femurs of transgenic mice were tougher, and their vertebral bodies were stiffer and stronger than those of wild-type mice. Lastly, osteocyte density was decreased in transgenic mice, suggesting that TGF-beta signaling in osteoblasts is required for normal osteoblast differentiation in vivo. Our results demonstrate that endogenous TGF-beta acts directly on osteoblasts to regulate bone remodeling, structure and biomechanical properties.

scholarly journals Targeted Inactivation of Rin3 Increases Trabecular Bone Mass by Reducing Bone Resorption and Favouring Bone Formation

2021 ◽  
Author(s):  
Mahéva Vallet ◽  
Antonia Sophocleous ◽  
Anna E. Törnqvist ◽  
Asim Azfer ◽  
Rob van’t Hof ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Wild Type ◽  
Common Genetic Variants ◽  
Trabecular Bone Mass ◽  
Skeletal Phenotype ◽  
Targeted Inactivation ◽  
Do So

AbstractCommon genetic variants at the RIN3 locus on chromosome 14q32 predispose to Paget’s disease of bone (PDB) but the mechanisms by which they do so are unknown. Here, we analysed the skeletal phenotype of female mice with targeted inactivation of the mouse Rin3 gene (Rin3−/−) as compared with wild-type littermates. The Rin3−/− mice had higher trabecular bone volume (BV/TV%) compared with wild type. Mean ± standard deviation values at the distal femur at 8 weeks were 9.0 ± 2.5 vs. 7.0 ± 1.5 (p = 0.002) and at 52 weeks were 15.8 ± 9.5 vs. 8.5 ± 4.2 (p = 0.002). No differences were observed in femoral cortical bone parameters with the exception of marrow diameter which was significantly smaller in 52-week-old Rin3−/− mice compared to wild type: (0.43 mm ± 0.1 vs. 0.57 mm ± 0.2 (p = 0.001). Bone histomorphometry showed a lower osteoclast surface / bone surface (Oc.S/BS%) at 8 weeks in Rin3−/− mice compared to wild type (24.1 ± 4.7 vs. 29.7 ± 6.6; p = 0.025) but there were no significant differences in markers of bone formation at this time. At 52 weeks, Oc.S/BS did not differ between genotypes but single labelled perimeter (SL.Pm/B.Pm (%)) was significantly higher in Rin3−/− mice (24.4 ± 6.4 vs. 16.5 ± 3.8, p = 0.003). We conclude that Rin3 negatively regulates trabecular bone mass in mice by inhibiting osteoclastic bone resorption and favouring bone formation. Our observations also suggest that the variants that predispose to PDB in humans probably do so by causing a gain-in-function of RIN3.

scholarly journals Disruption of the p53 Gene Results in Preserved Trabecular Bone Mass and Bone Formation After Mechanical Unloading

2002 ◽  
Vol 17 (1) ◽  
pp. 119-127 ◽  
Author(s):  
Akinori Sakai ◽  
Takeshi Sakata ◽  
Shinya Tanaka ◽  
Ryuji Okazaki ◽  
Naoki Kunugita ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
P53 Gene ◽  
Mechanical Unloading ◽  
Trabecular Bone Mass

scholarly journals Prolyl Hydroxylase Domain-Containing Protein 3 Gene Expression in Chondrocytes Is Not Essential for Bone Development in Mice

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2200
Author(s):  
Weirong Xing ◽  
Sheila Pourteymoor ◽  
Gustavo A. Gomez ◽  
Yian Chen ◽  
Subburaman Mohan
Keyword(s):  
Gene Expression ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Bone Volume ◽  
Endochondral Bone Formation ◽  
Chondrocyte Differentiation ◽  
Trabecular Bone Volume ◽  
Endochondral Bone ◽  
Trabecular Bone Mass

We previously showed that conditional disruption of the Phd2 gene in chondrocytes led to a massive increase in long bone trabecular bone mass. Loss of Phd2 gene expression or inhibition of PHD2 activity by a specific inhibitor resulted in a several-fold compensatory increase in Phd3 expression in chondrocytes. To determine if expression of PHD3 plays a role in endochondral bone formation, we conditionally disrupted the Phd3 gene in chondrocytes by crossing Phd3 floxed (Phd3flox/flox) mice with Col2α1-Cre mice. Loss of Phd3 expression in the chondrocytes of Cre+; Phd3flox/flox conditional knockout (cKO) mice was confirmed by real time PCR. At 16 weeks of age, neither body weight nor body length was significantly different in the Phd3 cKO mice compared to Cre−; Phd3flox/flox wild-type (WT) mice. Areal BMD measurements of total body as well as femur, tibia, and lumbar skeletal sites were not significantly different between the cKO and WT mice at 16 weeks of age. Micro-CT measurements revealed significant gender differences in the trabecular bone volume adjusted for tissue volume at the secondary spongiosa of the femur and the tibia for both genotypes, but no genotype difference was found for any of the trabecular bone measurements of either the femur or the tibia. Trabecular bone volume of distal femur epiphysis was not different between cKO and WT mice. Histology analyses revealed Phd3 cKO mice exhibited a comparable chondrocyte differentiation and proliferation, as evidenced by no changes in cartilage thickness and area in the cKO mice as compared to WT littermates. Consistent with the in vivo data, lentiviral shRNA-mediated knockdown of Phd3 expression in chondrocytes did not affect the expression of markers of chondrocyte differentiation (Col2, Col10, Acan, Sox9). Our study found that Phd2 but not Phd3 expressed in chondrocytes regulates endochondral bone formation, and the compensatory increase in Phd3 expression in the chondrocytes of Phd2 cKO mice is not the cause for increased trabecular bone mass in Phd2 cKO mice.

Prednisolone prevents decreases in trabecular bone mass and strength by reducing bone resorption and bone formation defect in adjuvant-induced arthritic rats

Bone ◽  
1998 ◽  
Vol 23 (4) ◽  
pp. 353-360 ◽  
Author(s):  
Y Okazaki ◽  
H Tsurukami ◽  
S Nishida ◽  
N Okimoto ◽  
S Aota ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Trabecular Bone Mass

scholarly journals The Type 2 Cannabinoid Receptor Regulates Bone Mass and Ovariectomy-Induced Bone Loss by Affecting Osteoblast Differentiation and Bone Formation

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2141-2149 ◽  
Author(s):  
Antonia Sophocleous ◽  
Euphemie Landao-Bassonga ◽  
Robert J. van‘t Hof ◽  
Aymen I. Idris ◽  
Stuart H. Ralston
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Osteoblast Differentiation ◽  
Cannabinoid Receptor ◽  
Nodule Formation ◽  
Wild Type

The type 2 cannabinoid receptor (CB2) has been reported to regulate bone mass and bone turnover but the mechanisms responsible are incompletely understood. In this study we investigated the role that the CB2 pathway plays in bone metabolism using a combination of genetic and pharmacological approaches. Bone mass and turnover were normal in young mice with targeted inactivation of CB2 receptor (CB2−/−), but by 12 months of age, they had developed high-turnover osteoporosis with relative uncoupling of bone resorption from bone formation. Primary osteoblasts from CB2−/− mice had a reduced capacity to form bone nodules in vitro when compared with cells from wild-type littermates and also had impaired PTH-induced alkaline phosphatase (ALP) activity. The CB2-selective agonist HU308 stimulated bone nodule formation in wild-type osteoblasts but had no effect in CB2−/− osteoblasts. Further studies in MC3T3-E1 osteoblast like cells showed that HU308 promoted cell migration and activated ERK phosphorylation, and these effects were blocked by the CB2 selective inverse agonist AM630. Finally, HU308 partially protected against ovariectomy induced bone loss in wild-type mice in vivo, primarily by stimulating bone formation, whereas no protective effects were observed in ovariectomized CB2−/− mice. These studies indicate that the CB2 regulates osteoblast differentiation in vitro and bone formation in vivo.

Arginine site 264 in murine estrogen receptor alpha is dispensable for the regulation of the skeleton

2020 ◽  
Author(s):  
Karin L. Gustafsson ◽  
Helen H. Farman ◽  
Karin H. Nilsson ◽  
Petra Henning ◽  
Sofia Movérare-Skrtic ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Thickness ◽  
Intracellular Signaling ◽  
Estrogen Receptor Alpha ◽  
Estrogen Treatment ◽  
Receptor Alpha ◽  
Trabecular Bone Mass

Estrogen protects against bone loss, but is not a suitable treatment due to adverse effects in other tissues. Increased knowledge regarding estrogen signaling in estrogen-responsive tissues is therefore warranted to aid the development of bone-specific estrogen treatments. Estrogen receptor alpha (ERα), the main mediator of estrogenic effects in bone, is widely subjected to posttranslational modifications (PTMs). In vitro studies have shown that methylation at site R260 in the human ERα affects receptor localization and intracellular signaling. The corresponding amino acid R264 in murine ERα has been shown to have a functional role in endothelium in vivo; albeit the methylation of R264 in the murine gene is yet to be empirically demonstrated. The aim of this study was to investigate if R264 in ERα is involved in the regulation of the skeleton in vivo. DXA analysis at three, six, nine, and twelve months of age showed no differences in total body areal BMD between R264A and WT in either female or male mice. Furthermore, analyses using CT demonstrated that trabecular bone mass in tibia and vertebra, and cortical thickness in tibia, were similar between R264A and WT mice. In addition, R264A females displayed a normal estrogen treatment response in trabecular bone mass, as well as in cortical thickness. Furthermore, uterus, thymus, and adipose tissue responded similarly in R264A and WT female mice after estrogen treatment. In conclusion, our novel finding that mutation of R264 in ERα does not affect the regulation of the skeleton, together with the known role of R264 for ERα-mediated endothelial effects, supports the concept that R264 determines tissue specificity of ERα.

scholarly journals Correction to: Targeted Inactivation of Rin3 Increases Trabecular Bone Mass by Reducing Bone Resorption and Favouring Bone Formation

2021 ◽  
Author(s):  
Mahéva Vallet ◽  
Antonia Sophocleous ◽  
Anna E. Törnqvist ◽  
Asim Azfer ◽  
Rob van’t Hof ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Trabecular Bone Mass ◽  
Targeted Inactivation

A correction to this paper has been published: https://doi.org/10.1007/s00223-021-00849-w

Abaloparatide, a novel osteoanabolic PTHrP analog, increases cortical and trabecular bone mass and architecture in orchiectomized rats by increasing bone formation without increasing bone resorption

Bone ◽  
2019 ◽  
Vol 120 ◽  
pp. 148-155 ◽  
Author(s):  
Heidi Chandler ◽  
Beate Lanske ◽  
Aurore Varela ◽  
Martin Guillot ◽  
Marilyne Boyer ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Trabecular Bone Mass
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