Modulation of osteoblast differentiation and bone mass by 5-HT2A receptor signaling in mice

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.

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The Molecular Mechanisms of Estrogen Receptor α on Two Single Nucleotide Polymorphisms to Regulate WNT Signaling in Osteoblasts

10.21007/etd.cghs.2021.0548 ◽

2021 ◽

Author(s):

◽

Sarocha Suthon ◽

Keyword(s):

Single Nucleotide Polymorphisms ◽

Bone Mass ◽

Wnt Signaling ◽

Signaling Pathway ◽

Osteoblast Differentiation ◽

Association Studies ◽

Wnt Signaling Pathway ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

Osteoporosis is the most common bone metabolic disorder, affecting over 200 million people globally. It is characterized by bone mass depletion and microarchitectural deterioration, leading to bone fragility and susceptibility to bone fracture. Genetic factors, estrogen deficiency, and dysregulation of the WNT signaling pathway contribute to the development of this disease. Genome-wide association studies have predicted that the single nucleotide polymorphisms (SNPs) rs2887571 and rs9921222 associate with low bone mass, but the mechanism of these SNPs has remained unknown. Analysis of osteoblasts from 112 different joint replacement patients reveals that the genotype of rs2887571 correlates with WNT5B expression, and the genotype of rs9921222 correlates with AXIN1 expression. Mechanistically, SNP rs2887571 has less binding of ERα and NFATc1 to allele A than allele G, resulting in more expression of WNT5B in homozygous AA than homozygous GG. Furthermore, WNT5B exhibits distinct effects from other WNTs on osteoblastogenesis. WNT5B increases mesenchymal stem cell proliferation, promotes adipogenesis, and suppresses osteoblast differentiation via ROR1/2, then activates DVL2/3, Rac1/Cdc42, JNK, and SIN3A signaling, as well as inhibits ROCK2 and β-catenin activity. For SNP rs9921222, homozygous TT has a higher expression of AXIN1 than homozygous CC. Molecular analysis shows that GATA4 favors binding at rs9921222 allele T to promote AXIN1 expression; in contrast, ERα prefers to bind at allele C to suppress the expression, resulting in more expression of AXIN1 in homozygous TT than homozygous CC. Functionally, the level of AXIN1 negatively correlates with the level of active β-catenin, which enhances osteoblast differentiation. Taken together, the biological mechanisms of SNPs rs2887571 and rs9921222, which are associated with osteoporosis via the WNT signaling pathway, are revealed, as well as the inhibitory effect of WNT5B on osteoblastogenesis. These data will be the fundamental knowledge for the development of osteoporosis prediction and therapeutic strategies.

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Faculty Opinions recommendation of Snail1 controls bone mass by regulating Runx2 and VDR expression during osteoblast differentiation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1149876.606961 ◽

2009 ◽

Author(s):

Paolo Bianco ◽

Mara Riminucci

Keyword(s):

Bone Mass ◽

Osteoblast Differentiation

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Regulation of body length and bone mass by Gpr126/Adgrg6

Science Advances ◽

10.1126/sciadv.aaz0368 ◽

2020 ◽

Vol 6 (12) ◽

pp. eaaz0368

Author(s):

Peng Sun ◽

Liang He ◽

Kunhang Jia ◽

Zhiying Yue ◽

Shichang Li ◽

...

Keyword(s):

Bone Formation ◽

Bone Mass ◽

Body Length ◽

Osteoblast Differentiation ◽

Body Height ◽

The Body ◽

Nucleotide Polymorphisms ◽

Type Iv ◽

And Function ◽

G Protein Coupled

Adhesion G protein–coupled receptor G6 (Adgrg6; also named GPR126) single-nucleotide polymorphisms are associated with human height in multiple populations. However, whether and how GPR126 regulates body height is unknown. In this study, we found that mouse body length was specifically decreased in Osx-Cre;Gpr126fl/fl mice. Deletion of Gpr126 in osteoblasts resulted in a remarkable delay in osteoblast differentiation and mineralization during embryonic bone formation. Postnatal bone formation, bone mass, and bone strength were also significantly affected in Gpr126 osteoblast deletion mice because of defects in osteoblast proliferation, differentiation, and ossification. Furthermore, type IV collagen functioned as an activating ligand of Gpr126 to regulate osteoblast differentiation and function by stimulating cAMP signaling. Moreover,the cAMP activator PTH(1–34), could partially restore the inhibition of osteoblast differentiation and the body length phenotype induced by Gpr126 deletion.Together, our results demonstrated that COLIV-Gpr126 regulated body length and bone mass through cAMP-CREB signaling pathway.

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Medicarpin, a legume phytoalexin, stimulates osteoblast differentiation and promotes peak bone mass achievement in rats: evidence for estrogen receptor β-mediated osteogenic action of medicarpin

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2010.11.002 ◽

2012 ◽

Vol 23 (1) ◽

pp. 27-38 ◽

Cited By ~ 39

Author(s):

Biju Bhargavan ◽

Divya Singh ◽

Abnish K. Gautam ◽

Jay Sharan Mishra ◽

Amit Kumar ◽

...

Keyword(s):

Estrogen Receptor ◽

Bone Mass ◽

Osteoblast Differentiation ◽

Peak Bone Mass ◽

Estrogen Receptor Β

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

Endocrinology ◽

10.1210/en.2010-0930 ◽

2011 ◽

Vol 152 (6) ◽

pp. 2141-2149 ◽

Cited By ~ 61

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.

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