The type 2 cannabinoid receptor (CB2) protects against age-related osteoporosis by affecting bone formation and CB2 agonists exhibit anabolic activity in vivo

Bone ◽  
2009 ◽  
Vol 44 ◽  
pp. S219 ◽  
Author(s):  
A. Sophocleous⁎ ◽  
E. Landao-Bassonga ◽  
R. van't Hof ◽  
S.H. Ralston ◽  
A.I. Idris
Keyword(s):  
Bone Formation ◽  
Cannabinoid Receptor ◽  
Anabolic Activity ◽  
Age Related

The type 2 cannabinoid receptor protects against age-related bone loss and ovariectomy induced bone loss by stimulating bone formation

Bone ◽  
2010 ◽  
Vol 47 ◽  
pp. S42-S43
Author(s):  
A. Sophocleous⁎ ◽  
E. Landao-Bassonga ◽  
R. van 't Hof ◽  
S.H. Ralston ◽  
A.I. Idris
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Cannabinoid Receptor ◽  
Age Related

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.

scholarly journals Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation

2020 ◽  
Vol 117 (49) ◽  
pp. 31070-31077 ◽  
Author(s):  
Nasir K. Bashiruddin ◽  
Mikihito Hayashi ◽  
Masanobu Nagano ◽  
Yan Wu ◽  
Yukiko Matsunaga ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Cyclic Peptides ◽  
Treatment Options ◽  
Affinity Maturation ◽  
Great Promise ◽  
Anabolic Activity ◽  
Anabolic Treatment ◽  
Increase Bone Formation

Osteoporosis is caused by a disequilibrium between bone resorption and bone formation. Therapeutics for osteoporosis can be divided into antiresorptives that suppress bone resorption and anabolics which increase bone formation. Currently, the only anabolic treatment options are parathyroid hormone mimetics or an anti-sclerostin monoclonal antibody. With the current global increases in demographics at risk for osteoporosis, development of therapeutics that elicit anabolic activity through alternative mechanisms is imperative. Blockade of the PlexinB1 and Semaphorin4D interaction on osteoblasts has been shown to be a promising mechanism to increase bone formation. Here we report the discovery of cyclic peptides by a novel RaPID (Random nonstandard Peptides Integrated Discovery) system-based affinity maturation methodology that generated the peptide PB1m6A9 which binds with high affinity to both human and mouse PlexinB1. The chemically dimerized peptide, PB1d6A9, showed potent inhibition of PlexinB1 signaling in mouse primary osteoblast cultures, resulting in significant enhancement of bone formation even compared to non-Semaphorin4D–treated controls. This high anabolic activity was also observed in vivo when the lipidated PB1d6A9 (PB1d6A9-Pal) was intravenously administered once weekly to ovariectomized mice, leading to complete rescue of bone loss. The potent osteogenic properties of this peptide shows great promise as an addition to the current anabolic treatment options for bone diseases such as osteoporosis.

Characterization of bladder function in a cannabinoid receptor type 2 knockout mouse in vivo and in vitro

2013 ◽  
Vol 33 (5) ◽  
pp. 566-570 ◽  
Author(s):  
Lysanne Campeau ◽  
Claudius Füllhase ◽  
Norifumi Sawada ◽  
Christian Gratzke ◽  
Petter Hedlund ◽  
...  
Keyword(s):  
Knockout Mouse ◽  
Cannabinoid Receptor ◽  
Receptor Type ◽  
Bladder Function ◽  
Cannabinoid Receptor Type 2

scholarly journals HDAC6 inactivates Runx2 promoter to block osteogenesis of bone marrow stromal cells in age-related bone loss of mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chao Ma ◽  
Juan Gao ◽  
Jun Liang ◽  
Weixiang Dai ◽  
Zhenfei Wang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Differentiation Potential ◽  
Runx2 Expression ◽  
Aged Mice ◽  
Age Related ◽  
Old Mice

Abstract Background Senile osteoporosis can cause bone fragility and increased risk for fractures and has been one of the most prevalent and severe diseases affecting the elderly population worldwidely. The underlying mechanisms are currently intensive areas of investigation. In age-related bone loss, decreased bone formation overweighs increased bone resorption. The molecular mechanisms underlying defective bone formation in age-related bone loss are not completely understood. In particular, the specific role of histone acetylation in age-related bone loss has not been examined thoroughly. Methods We employed 6- and 18-month-old mice to investigate the mechanisms of defective bone formation in age-related bone loss. Bone marrow stromal cells (BMSCs) were induced to undergo in vitro osteogenic differentiation. Chromatin immunoprecipitation (ChIP) was used to investigate the binding of histone deacetylases (HDACs) on Runx2 promoter in BMSCs. Luciferase reporter and transient transfection assay were employed to study Runx2 gene expression modulation by HDAC and androgen receptor (AR). siRNA and HDAC6 inhibitor, Tubastatin A, were used to inhibit HDAC6 in vitro. And systemic administration of Tubastatin A was used to block HDAC6 in vivo. Results Age-related trabecular bone loss was observed in 18-month-old mice compared with 6-month-old mice. In vitro osteogenic differentiation potential of BMSCs from 18-month-old mice was weaker than 6-month-old mice, in which there was Runx2 expression inactivation in BMSCs of 18-month-old mice compared with 6-month-old mice, which was attributable to HDAC6-mediated histone hypoacetylation in Runx2 promoter. There was competitive binding of HDAC6 and AR on Runx2 promoter to modulate Runx2 expression in BMSCs. More importantly, through siRNA- or specific inhibitor-mediated HDAC6 inhibition, we could activate Runx2 expression, rescue in vitro osteogenesis potential of BMSCs, and alleviate in vivo age-related bone loss of mice. Conclusion HDAC6 accumulation and histone hypoacetylation on Runx2 promoter contributed to the attenuation of in vitro osteogenic differentiation potential of BMSCs from aged mice. Through HDAC6 inhibition, we could activate Runx2 expression and osteogenic differentiation potential of BMSCs from aged mice and alleviate the age-related bone loss of aged mice. Our study will benefit not only for understanding the age-related bone loss, but also for finding new therapies to treat senile osteoporosis.

Involvement of cannabinoid receptor type 2 in light-induced degeneration of cells from mouse retinal cell line in vitro and mouse photoreceptors in vivo

2018 ◽  
Vol 167 ◽  
pp. 44-50 ◽  
Author(s):  
Tomoyo Imamura ◽  
Kazuhiro Tsuruma ◽  
Yuki Inoue ◽  
Tomohiro Otsuka ◽  
Yuta Ohno ◽  
...  
Keyword(s):  
Cell Line ◽  
Cannabinoid Receptor ◽  
Receptor Type ◽  
Retinal Cell ◽  
Cannabinoid Receptor Type 2

scholarly journals An Irradiation-Altered Bone Marrow Microenvironment Impacts Anabolic Actions of PTH

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4525-4536 ◽  
Author(s):  
A. J. Koh ◽  
C. M. Novince ◽  
X. Li ◽  
T. Wang ◽  
R. S. Taichman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Bone Marrow Microenvironment ◽  
Fibroblast Growth Factor 2 ◽  
Mrna Levels ◽  
Hematopoietic Stem ◽  
Cell Recruitment ◽  
Anabolic Activity ◽  
Marrow Cellularity

PTH stimulates bone formation and increases hematopoietic stem cells through mechanisms as yet uncertain. The purpose of this study was to identify mechanisms by which PTH links actions on cells of hematopoietic origin with osteoblast-mediated bone formation. C57B6 mice (10 d) were nonlethally irradiated and then administered PTH for 5–20 d. Irradiation reduced bone marrow cellularity with retention of cells lining trabeculae. PTH anabolic activity was greater in irradiated vs. nonirradiated mice, which could not be accounted for by altered osteoblasts directly or osteoclasts but instead via an altered bone marrow microenvironment. Irradiation increased fibroblast growth factor 2, TGFβ, and IL-6 mRNA levels in the bone marrow in vivo. Irradiation decreased B220 cell numbers, whereas the percent of Lin−Sca-1+c-kit+ (LSK), CD11b+, CD68+, CD41+, Lin−CD29+Sca-1+ cells, and proliferating CD45−Nestin+ cells was increased. Megakaryocyte numbers were reduced with irradiation and located more closely to trabecular surfaces with irradiation and PTH. Bone marrow TGFβ was increased in irradiated PTH-treated mice, and inhibition of TGFβ blocked the PTH augmentation of bone in irradiated mice. In conclusion, irradiation created a permissive environment for anabolic actions of PTH that was TGFβ dependent but osteoclast independent and suggests that a nonosteoclast source of TGFβ drives mesenchymal stem cell recruitment to support PTH anabolic actions.

scholarly journals CGRP Regulates the Age-Related Switch Between Osteoblast and Adipocyte Differentiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Hang Li ◽  
Jian Qu ◽  
Haihong Zhu ◽  
Jiaojiao Wang ◽  
Hao He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Adipogenic Differentiation ◽  
Differentiation Potential ◽  
Aged Mice ◽  
Age Related ◽  
Calcitonin Gene

Osteoporosis is a chronic age-related disease. During aging, bone marrow-derived mesenchymal stem cells (BMSCs) display increased adipogenic, along with decreased osteogenic, differentiation capacity. The aim of the present study was to investigate the effect of calcitonin gene-related peptide (CGRP) on the osteogenic and adipogenic differentiation potential of BMSC-derived osteoblasts. Here, we found that the level of CGRP was markedly lower in bone marrow supernatant from aged mice compared with that in young mice. In vitro experiments indicated that CGRP promoted the osteogenic differentiation of BMSCs while inhibiting their adipogenic differentiation. Compared with vehicle-treated controls, aged mice treated with CGRP showed a substantial promotion of bone formation and a reduction in fat accumulation in the bone marrow. Similarly, we found that CGRP could significantly enhance bone formation in ovariectomized (OVX) mice in vivo. Together, our results suggested that CGRP may be a key regulator of the age-related switch between osteogenesis and adipogenesis in BMSCs and may represent a potential therapeutic strategy for the treatment of age-related bone loss.

Sign in / Sign up

Export Citation Format

Share Document