The atypical anti-psychotic clozapine decreases bone mass in rats in vivo

AbstractMicroRNAs (miRNAs) are short (18–24 nucleotides) non-coding RNA sequences that regulate gene expression via binding of messenger RNA. It is estimated that miRNAs co-regulate the expression of more than 70% of all human genes, many of which fulfil important roles in bone metabolism and muscle function. In-vitro and in-vivo experiments have shown that the targeted loss of miRNAs in distinct bone cell types (osteoblasts and osteoclasts) results in altered bone mass and bone architecture. These results emphasize the biological relevance of miRNAs for bone health.MiRNAs are not only considered as novel bone biomarkers because of their biological importance to bone metabolism, but also on the basis of other favorable properties: 1) Secretion of miRNAs from cells enables “minimally invasive” detection in biological fluids such as serum. 2) High stability of miRNAs in serum enables the retrospective analysis of frozen blood specimens. 3) Quantification of miRNAs in the serum is based on the RT-PCR - a robust method that is considered as the gold standard for the analysis of nucleic acids in clinical diagnostics.With regard to osteoporosis, it has been shown that many of the known risk factors are characterized by distinct miRNA profiles in the affected tissues: i) age-related loss of bone mass, ii) sarcopenia, iii) changes in estrogen metabolism and related changes Loss of bone mass, and iv) diabetes. Therefore, numerous studies in recent years have dealt with the characterization of miRNAs in the serum of osteoporosis patients and healthy controls, and were able to identify recurring miRNA patterns that are characteristic of osteoporosis. These novel biomarkers have great potential for the diagnosis and prognosis of osteoporosis and its clinical outcomes.The aim of this article is to give a summary of the current state of knowledge on the research and application of miRNA biomarkers in osteoporosis.

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Effect of nitric oxide synthase inhibitors on bone metabolism in growing rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.5.e840 ◽

1996 ◽

Vol 270 (5) ◽

pp. E840-E845 ◽

Cited By ~ 5

Author(s):

H. Tsukahara ◽

M. Miura ◽

S. Tsuchida ◽

I. Hata ◽

K. Hata ◽

...

Keyword(s):

Nitric Oxide ◽

Bone Mass ◽

Bone Mineral ◽

Normal Serum ◽

Bone Mineral Status ◽

Growing Rats ◽

Bone Mineral Mass ◽

Bone Degradation ◽

Cross Links

We examined the effects of chronic nitric oxide (NO) blockade on bone mineral status in growing rats. Oral administration of NG-nitro-L-arginine methyl ester (L-NAME) for 4 wk caused hypertension and a significant reduction in urinary NO2- and NO3- excretion. Four-week oral aminoguanidine (AG, 400 mg/dl of drinking water) did not alter blood pressure but caused a significant decrease in urinary NO2- and NO3-. Rats treated with L-NAME at doses of 20 and 50 mg/dl had normal bone mineral mass in the lumbar spine, but the highest dose (80 mg/dl) caused a slight decrease in bone mass. Chronic AG induced a significant spine osteopenia. This effect of AG was abolished by the simultaneous administration of L-arginine (2.0 g/dl). AG-induced osteopenia was associated with a significant increase in urine excretion of collagen cross-links with normal serum osteocalcin. These findings indicate that chronic AG administration can cause an imbalance between bone resorption and formation, resulting in a decrease in bone mass in growing rats, and suggest that NO produced by inducible NO synthase plays an important role in basal osteoclast bone degradation activity in vivo.

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Increased Bone Mass in Mice Lacking the Adipokine Apelin

Endocrinology ◽

10.1210/en.2012-2034 ◽

2013 ◽

Vol 154 (6) ◽

pp. 2069-2080 ◽

Cited By ~ 22

Author(s):

Lalita Wattanachanya ◽

Wei-Dar Lu ◽

Ramendra K. Kundu ◽

Liping Wang ◽

Marcia J. Abbott ◽

...

Keyword(s):

Bone Mass ◽

Bone Cells ◽

Physiological Role ◽

In Vitro Study ◽

Maximum Effect ◽

Dependent Manner ◽

Primary Mouse ◽

Skeletal Homeostasis

Abstract Adipose tissue plays an important role in skeletal homeostasis, and there is interest in identifying adipokines that influence bone mass. One such adipokine may be apelin, a ligand for the Gi-G protein-coupled receptor APJ, which has been reported to enhance mitogenesis and suppress apoptosis in MC3T3-E1 cells and primary human osteoblasts (OBs). However, it is unclear whether apelin plays a physiological role in regulating skeletal homeostasis in vivo. In this study, we compared the skeletal phenotypes of apelin knockout (APKO) and wild-type mice and investigated the direct effects of apelin on bone cells in vitro. The increased fractional cancellous bone volume at the distal femur was observed in APKO mice of both genders at 12 weeks of age and persisted until the age of 20. Cortical bone perimeter at the femoral midshaft was significantly increased in males and females at both time points. Dynamic histomorphometry revealed that APKO mice had increased rates of bone formation and mineral apposition, with evidences of accelerated OB proliferation and differentiation, without significant alteration in osteoclast activity. An in vitro study showed that apelin increased proliferation of primary mouse OBs as well as suppressed apoptosis in a dose-dependent manner with the maximum effect at 5nM. However, it had no effect on the formation of mineralized nodules. We did not observed significantly altered in osteoclast parameters in vitro. Taken together, the increased bone mass in mice lacking apelin suggested complex direct and paracrine/endocrine effects of apelin on bone, possibly via modulating insulin sensitivity. These results indicate that apelin functions as a physiologically significant antianabolic factor in bone in vivo.

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Cortical bone adaptation to a moderate level of mechanical loading in male Sost deficient mice

Scientific Reports ◽

10.1038/s41598-020-79098-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Haisheng Yang ◽

Alexander Büttner ◽

Laia Albiol ◽

Catherine Julien ◽

Tobias Thiele ◽

...

Keyword(s):

Physical Activity ◽

Bone Formation ◽

Bone Mass ◽

Cortical Bone ◽

Bone Adaptation ◽

Moderate Level ◽

Skeletal Maturation ◽

Male Mice ◽

Males And Females

AbstractLoss-of-function mutations in the Sost gene lead to high bone mass phenotypes. Pharmacological inhibition of Sost/sclerostin provides a new drug strategy for treating osteoporosis. Questions remain as to how physical activity may affect bone mass under sclerostin inhibition and if that effect differs between males and females. We previously observed in female Sost knockout (KO) mice an enhanced cortical bone formation response to a moderate level of applied loading (900 με at the tibial midshaft). The purpose of the present study was to examine cortical bone adaptation to the same strain level applied to male Sost KO mice. Strain-matched in vivo compressive loading was applied to the tibiae of 10-, 26- and 52-week-old male Sost KO and littermate control (LC) mice. The effect of tibial loading on bone (re)modeling was measured by microCT, 3D time-lapse in vivo morphometry, 2D histomorphometry and gene expression analyses. As expected, Sost deficiency led to high cortical bone mass in 10- and 26-week-old male mice as a result of increased bone formation. However, the enhanced bone formation associated with Sost deficiency did not appear to diminish with skeletal maturation. An increase in bone resorption was observed with skeletal maturation in male LC and Sost KO mice. Two weeks of in vivo loading (900 με at the tibial midshaft) induced only a mild anabolic response in 10- and 26-week-old male mice, independent of Sost deficiency. A decrease in the Wnt inhibitor Dkk1 expression was observed 3 h after loading in 52-week-old Sost KO and LC mice, and an increase in Lef1 expression was observed 8 h after loading in 10-week-old Sost KO mice. The current results suggest that long-term inhibition of sclerostin in male mice does not influence the adaptive response of cortical bone to moderate levels of loading. In contrast with our previous strain-matched study in females showing enhanced bone responses with Sost ablation, these results in males indicate that the influence of Sost deficiency on the cortical bone formation response to a moderate level of loading differs between males and females. Clinical studies examining antibodies to inhibit sclerostin may need to consider that the efficacy of additional physical activity regimens may be sex dependent.

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Sclareol prevents ovariectomy-induced bone loss in vivo and inhibits osteoclastogenesis in vitro via suppressing NF-κB and MAPK/ERK signaling pathways

Food & Function ◽

10.1039/c9fo00206e ◽

2019 ◽

Vol 10 (10) ◽

pp. 6556-6567 ◽

Cited By ~ 5

Author(s):

Haiming Jin ◽

Zhenxuan Shao ◽

Qingqing Wang ◽

Jiansen Miao ◽

Xueqin Bai ◽

...

Keyword(s):

Bone Loss ◽

Bone Mass ◽

Postmenopausal Women ◽

Postmenopausal Osteoporosis ◽

Bone Quality ◽

Progressive Disease ◽

Erk Signaling ◽

Low Bone Mass

Postmenopausal osteoporosis (PMO) is a progressive disease occurring in elderly postmenopausal women that is characterized by low bone mass and impaired bone quality.

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Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival

The Journal of Cell Biology ◽

10.1083/jcb.201204067 ◽

2012 ◽

Vol 199 (7) ◽

pp. 1145-1158 ◽

Cited By ~ 42

Author(s):

Hyung Joon Kim ◽

Vikram Prasad ◽

Seok-Won Hyung ◽

Zang Hee Lee ◽

Sang-Won Lee ◽

...

Keyword(s):

Plasma Membrane ◽

Bone Mass ◽

Osteoclast Differentiation ◽

Premenopausal Women ◽

Fine Tuning ◽

Bone Homeostasis ◽

Regulatory Loop ◽

And Function

The precise regulation of Ca2+ dynamics is crucial for proper differentiation and function of osteoclasts. Here we show the involvement of plasma membrane Ca2+ ATPase (PMCA) isoforms 1 and 4 in osteoclastogenesis. In immature/undifferentiated cells, PMCAs inhibited receptor activator of NF-κB ligand–induced Ca2+ oscillations and osteoclast differentiation in vitro. Interestingly, nuclear factor of activated T cell c1 (NFATc1) directly stimulated PMCA transcription, whereas the PMCA-mediated Ca2+ efflux prevented NFATc1 activation, forming a negative regulatory loop. PMCA4 also had an anti-osteoclastogenic effect by reducing NO, which facilitates preosteoclast fusion. In addition to their role in immature cells, increased expression of PMCAs in mature osteoclasts prevented osteoclast apoptosis both in vitro and in vivo. Mice heterozygous for PMCA1 or null for PMCA4 showed an osteopenic phenotype with more osteoclasts on bone surface. Furthermore, PMCA4 expression levels correlated with peak bone mass in premenopausal women. Thus, our results suggest that PMCAs play important roles for the regulation of bone homeostasis in both mice and humans by modulating Ca2+ signaling in osteoclasts.

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B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo

Blood ◽

10.1182/blood-2006-07-037994 ◽

2007 ◽

Vol 109 (9) ◽

pp. 3839-3848 ◽

Cited By ~ 269

Author(s):

Yan Li ◽

Gianluca Toraldo ◽

Aimin Li ◽

Xiaoying Yang ◽

Hongying Zhang ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Bone Mass ◽

B Cell ◽

Peak Bone Mass ◽

Bone Destruction ◽

Enzyme Linked Immunosorbent Assay ◽

Bone Homeostasis ◽

Basal Bone

Abstract Bone homeostasis is regulated by a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclastogenesis is controlled by the ratio of receptor activator of NF-κB ligand (RANKL) relative to its decoy receptor, osteoprotegerin (OPG). The source of OPG has historically been attributed to osteoblasts (OBs). While activated lymphocytes play established roles in pathological bone destruction, no role for lymphocytes in basal bone homeostasis in vivo has been described. Using immunomagnetic isolation of bone marrow (BM) B cells and B-cell precursor populations and quantitation of their OPG production by enzyme-linked immunosorbent assay (ELISA) and real-time reverse transcriptase–polymerase chain reaction (RT-PCR), cells of the B lineage were found to be responsible for 64% of total BM OPG production, with 45% derived from mature B cells. Consistently B-cell knockout (KO) mice were found to be osteoporotic and deficient in BM OPG, phenomena rescued by B-cell reconstitution. Furthermore, T cells, through CD40 ligand (CD40L) to CD40 costimulation, promote OPG production by B cells in vivo. Consequently, T-cell–deficient nude mice, CD40 KO mice, and CD40L KO mice display osteoporosis and diminished BM OPG production. Our data suggest that lymphocytes are essential stabilizers of basal bone turnover and critical regulators of peak bone mass in vivo.

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In vivo measurement of bone mass. Its use in demineralized states such as osteoporosis

JAMA ◽

10.1001/jama.219.3.325 ◽

1972 ◽

Vol 219 (3) ◽

pp. 325-329 ◽

Cited By ~ 13

Author(s):

D. M. Smith

Keyword(s):

Bone Mass ◽

In Vivo Measurement

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Bromodomain Protein BRD4 Accelerates Glucocorticoid Dysregulation of Bone Mass and Marrow Adiposis by Modulating H3K9 and Foxp1

Cells ◽

10.3390/cells9061500 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1500

Author(s):

Feng-Sheng Wang ◽

Yu-Shan Chen ◽

Jih-Yang Ko ◽

Chung-Wen Kuo ◽

Huei-Jing Ke ◽

...

Keyword(s):

Bone Mass ◽

Mass Loss ◽

Osteogenic Differentiation ◽

Progenitor Cells ◽

Mesenchymal Progenitor Cells ◽

Marrow Fat ◽

Bone Mass Loss ◽

Brd4 Inhibition ◽

The Cost

Glucocorticoid provokes bone mass loss and fatty marrow, accelerating osteoporosis development. Bromodomain protein BRD4, an acetyl–histone-binding chromatin reader, regulates stem cell and tissue homeostasis. We uncovered that glucocorticoid inhibited acetyl Lys-9 at the histone 3 (H3K9ac)-binding Runx2 promoter and decreased osteogenic differentiation, whereas bromodomain protein 4 (BRD4) and adipocyte formation were upregulated in bone-marrow mesenchymal progenitor cells. BRD4 knockdown improved H3K9ac occupation at the Runx2 promoter and osteogenesis, but attenuated glucocorticoid-mediated adipocyte formation together with the unaffected H3K9ac-binding PPARγ2 promoter. BRD4 regulated epigenome related to fatty acid metabolism and the forkhead box P1 (Foxp1) pathway, which occupied the PPARγ2 promoter to modulate glucocorticoid-induced adipocytic activity. In vivo, BRD4 inhibitor JQ-1 treatment mitigated methylprednisolone-induced suppression of bone mass, trabecular microstructure, mineral acquisition, and osteogenic differentiation. Foxp1 signaling, marrow fat, and adipocyte formation in glucocorticoid-treated skeleton were reversed upon JQ-1 treatment. Taken together, glucocorticoid-induced H3K9 hypoacetylation augmented BRD4 action to Foxp1, which steered mesenchymal progenitor cells toward adipocytes at the cost of osteogenic differentiation in osteoporotic skeletons. BRD4 inhibition slowed bone mass loss and marrow adiposity. Collective investigations convey a new epigenetic insight into acetyl histone reader BRD4 control of osteogenesis and adipogenesis in skeleton, and highlight the remedial effects of the BRD4 inhibitor on glucocorticoid-induced osteoporosis.

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