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1.  Serotonin 2B Receptor (5-HT2B R) Signals through Prostacyclin and PPAR-ß/δ in Osteoblasts 
PLoS ONE  2013;8(9):e75783.
Osteoporosis is due to an imbalance between decreased bone formation by osteoblasts and increased resorption by osteoclasts. Deciphering factors controlling bone formation is therefore of utmost importance for the understanding and the treatment of osteoporosis. Our previous in vivo results showed that bone formation is reduced in the absence of the serotonin receptor 5-HT2B, causing impaired osteoblast proliferation, recruitment, and matrix mineralization. In this study, we investigated the signaling pathways responsible for the osteoblast defect in 5-HT2BR−/− mice. Notably, we investigated the phospholipase A2 pathway and synthesis of eicosanoids in 5-HT2BR−/− compared to wild type (WT) osteoblasts. Compared to control osteoblasts, the lack of 5-HT2B receptors was only associated with a 10-fold over-production of prostacyclin (PGI2). Also, a specific prostacyclin synthase inhibitor (U51605) rescued totally osteoblast aggregation and matrix mineralization in the 5-HT2BR−/− osteoblasts without having any effect on WT osteoblasts. Prostacyclin is the endogenous ligand of the nuclear peroxisome proliferator activated receptor ß/δ (PPAR-ß/δ), and its inhibition in 5-HT2BR−/− cells rescued totally the alkaline phosphatase and osteopontin mRNA levels, cell-cell adhesion, and matrix mineralization. We conclude that the absence of 5-HT2B receptors leads to the overproduction of prostacyclin, inducing reduced osteoblast differentiation due to PPAR-ß/δ -dependent target regulation and defective cell-cell adhesion and matrix mineralization. This study thus reveals a previously unrecognized cell autonomous osteoblast defect in the absence of 5-HT2BR and highlights a new pathway linking 5-HT2B receptors and nuclear PPAR- ß/δ via prostacyclin.
doi:10.1371/journal.pone.0075783
PMCID: PMC3775737  PMID: 24069449
2.  Serotonin: good or bad for bone 
BoneKEy reports  2012;1:120.
Besides its action as a neurotransmitter, serotonin has multiple physiological functions in several peripheral organs. Recently, Yadav et al. suggested that peripheral serotonin produced in the gut was a major negative regulator of osteoblast proliferation. These data were challenged by Cui et al. that showed no change in bone density in mature mice with a global invalidation of tryptophan hydroxylase 1, the enzyme responsible of serotonin synthesis in the periphery. In this context, we showed that osteoclasts are able to synthetize serotonin that acts locally to induce osteoclast precursors differentiation. Our data and previous results from others suggest that rather than acting as a hormone, serotonin produced in the bone could act locally on osteoclast and osteoblast realizing in the bone a complete micro-serotoninergic system.
doi:10.1038/bonekey.2012.120
PMCID: PMC3727814  PMID: 23951501
3.  Does hormone replacement therapy prevent lateral rotatory spondylolisthesis in postmenopausal women? 
European Spine Journal  2011;21(6):1127-1134.
Purpose
Degenerative scoliosis usually begins at menopause and lateral rotatory olisthesis (LRO) might be a triggering factor in the onset of degenerative scoliosis in postmenopausal women. We set out to evaluate the influence of hormone replacement therapy (HRT) on degenerative scoliosis and on LRO.
Methods
A cross-sectional study was conducted in 146 postmenopausal women: 75 women had received HRT for more than 1 year (HRT > 1) and 71 women had never received HRT or less than 1 year (HRT < 1). Scoliotic curve, LRO, sacral slope, lordosis, kyphosis were measured. The excess risk of LRO associated with age, BMI, isometric strength of brachial biceps, bone mineral density, lean mass and HRT was evaluated using a multiple logistic regression model.
Results
No difference was found in sacral slope, lumbar lordosis or thoracic kyphosis between both groups or in the presence of scoliosis. The prevalence of LRO was significantly lower in HRT >1 than HRT <1 (8 vs. 30%) while the risk was dependent on age, HRT and their interaction. LRO increased with age only in HRT <1 (11% when aged ≤66 years vs. 39% when aged >66 years, p = 0.013), whereas the prevalence of LRO remained stable in HRT >1.
Conclusions
LRO was significantly lower in women who received HRT. The excess risk of LRO was dependent on both age and HRT status. These findings suggest that HRT might prevent the onset of LRO, and therefore might contribute to the prevention of low back pain.
doi:10.1007/s00586-011-2048-3
PMCID: PMC3366144  PMID: 22033571
Lateral spondylolisthesis; Scoliosis; Hormone replacement therapy
4.  Alteration of proteoglycan sulfation affects bone growth and remodeling 
Bone  2013;54(1):83-91.
Diastrophic dysplasia (DTD) is a chondrodysplasia caused by mutations in the SLC26A2 gene, leading to reduced intracellular sulfate pool in chondrocytes, osteoblasts and fibroblasts. Hence, proteoglycans are undersulfated in the cartilage and bone of DTD patients. To characterize the bone phenotype of this skeletal dysplasia we used the Slc26a2 knock-in mouse (dtd mouse), that was previously validated as an animal model of DTD in humans.
X-rays, bone densitometry, static and dynamic histomorphometry, and in vitro studies revealed a primary bone defect in the dtd mouse model.
We showed in vivo that this primary bone defect in dtd mice is due to decreased bone accrual associated with a decreased trabecular and periosteal appositional rate at the cell level in one month-old mice. Although the osteoclast number evaluated by histomorphometry was not different in dtd compared to wild-type mice, urine analysis of deoxypyridinoline cross-links and serum levels of type I collagen C-terminal telopeptides showed a higher resorption rate in dtd mice compared to wild-type littermates. Electron microscopy studies showed that collagen fibrils in bone were thinner and less organized in dtd compared to wild-type mice. These data suggest that the low bone mass observed in mutant mice could possibly be linked to the different bone matrix compositions/organizations in dtd mice triggering changes in osteoblast and osteoclast activities.
Overall, these results suggest that proteoglycan undersulfation not only affects the properties of hyaline cartilage, but can also lead to unbalanced bone modeling and remodeling activities, demonstrating the importance of proteoglycan sulfation in bone homeostasis.
Highlights
► The osteopenic phenotype in a mouse model of proteoglycan undersulfation has been characterized. ► In vivo and in vitro studies revealed a primary bone defect in the dtd mouse model. ► Low bone mass in mutant mice is linked to bone matrix alterations triggering changes in osteoblast and osteoclast activities. ► Electron microscopy showed that collagen fibrils were thinner and less organized in mutant compared to wild-type mice. ► Results demonstrate that the SLC26A2 gene not only affects chondrogenesis, but also leads to unbalanced bone modeling and remodeling activities.
doi:10.1016/j.bone.2013.01.036
PMCID: PMC3607217  PMID: 23369989
BER, bone elongation rate; BFR, bone formation rate; BMC, bone mineral content; BMD, bone mineral density; BrdU, 5-bromo-2′-deoxyuridine; CTX, C-terminal telopeptides of type I collagen; DEXA, dual energy X-ray absorptiometry; DLS/BS, double labeled surface per bone surface; DPD, deoxypyridinoline; DTD, diastrophic dysplasia; DTDST, diastrophic dysplasia sulfate transporter; FCS, fetal calf serum; MAR, mineral apposition rate; M-CSF, macrophage colony-stimulating factor; P, postnatal day; PBS, phosphate buffer saline; PTH, parathyroid hormone; RANK-L, receptor activator of nuclear factor kappa-B ligand; SLC26A2, solute carrier family 26 member 2; TRAP, tartrate resistant acid phosphatase; Diastrophic dysplasia; Proteoglycan; Bone histomorphometry; Animal models; Osteoclasts; Osteoblasts
5.  Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD 
Our specific aims were to evaluate the power of bivariate analysis and to compare its performance with traditional univariate analysis in samples of unrelated subjects under varying sampling selection designs. Bivariate association analysis was based on the seemingly unrelated regression (SUR) model that allows different genetic models for different traits. We conducted extensive simulations for the case of two correlated quantitative phenotypes, with the quantitative trait locus making equal or unequal contributions to each phenotype. Our simulation results confirmed that the power of bivariate analysis is affected by the size, direction and source of the phenotypic correlations between traits. They also showed that the optimal sampling scheme depends on the size and direction of the induced genetic correlation. In addition, we demonstrated the efficacy of SUR-based bivariate test by applying it to a real Genome-Wide Association Study (GWAS) of Bone Mineral Density (BMD) values measured at the lumbar spine (LS) and at the femoral neck (FN) in a sample of unrelated males with low BMD (LS Z-scores ≤−2) and with high BMD (LS and FN Z-scores >0.5). A substantial amount of top hits in bivariate analysis did not reach nominal significance in any of the two single-trait analyses. Altogether, our studies suggest that bivariate analysis is of practical significance for GWAS of correlated phenotypes.
doi:10.1038/ejhg.2011.22
PMCID: PMC3110051  PMID: 21427758
bivariate association; GWAS; BMD; osteoporosis
6.  Targeting Bone Alleviates Osteoarthritis in Osteopenic Mice and Modulates Cartilage Catabolism 
PLoS ONE  2012;7(3):e33543.
Objective
Subchondral bone modifications occur early in the development of osteoarthritis (OA). The level of bone resorption might impact cartilage remodeling. We therefore assessed the in vivo and in vitro effects of targeting bone resorption in OA and cartilage metabolism.
Methods
OA was induced by meniscectomy (MNX) in ovariectomized osteopenic mice (OP) treated with estradiol (E2), pamidronate (PAM), or phosphate buffered saline (PBS) for 6 weeks. We assessed the subchondral bone and cartilage structure and the expression of cartilage matrix proteases. To assess the involvement of bone soluble factors in cartilage metabolism, supernatant of human bone explants pre-treated with E2 or PAM were transferred to cartilage explants to assess proteoglycan release and aggrecan cleavage. OPG/RANKL mRNA expression was assessed in bone explants by real-time quantitative PCR. The role of osteoprotegerin (OPG) in the bone-cartilage crosstalk was tested using an OPG neutralizing antibody.
Results
Bone mineral density of OP mice and osteoclast number were restored by E2 and PAM (p<0.05). In OP mice, E2 and PAM decreased ADAMTS-4 and -5 expression, while only PAM markedly reduced OA compared to PBS (2.0±0.63 vs 5.2±0.95; p<0.05). OPG/RANKL mRNA was increased in human bone explants treated with both drugs (2.2–3.7-fold). Moreover, supernatants from bone explants cultured with E2 or PAM reduced aggrecan cleavage and cartilage proteoglycan release (73±8.0% and 80±22% of control, respectively, p<0.05). This effect was reversed with osteoprotegerin blockade.
Conclusion
The inhibition of bone resorption by pamidronate in osteopenic mice alleviates the histological OA score with a reduction in the expression of aggrecanases. Bone soluble factors, such as osteoprotegerin, impact the cartilage response to catabolic factors. This study further highlights the importance of subchondral bone in the regulation of joint cartilage damage in OA.
doi:10.1371/journal.pone.0033543
PMCID: PMC3303845  PMID: 22432033
7.  Fracture risk and the use of a diuretic (indapamide sr) ± perindopril: a substudy of the Hypertension in the Very Elderly Trial (HYVET) 
Trials  2006;7:33.
Background
The Hypertension in the Very Elderly Trial (HYVET) is a placebo controlled double blind trial of treating hypertension with indapamide Slow Release (SR) ± perindopril in subjects over the age of 80 years. The primary endpoints are stroke (fatal and non fatal). In view of the fact that thiazide diuretics and indapamide reduce urinary calcium and may increase bone mineral density, a fracture sub study was designed to investigate whether or not the trial anti-hypertensive treatment will reduce the fracture rate in very elderly hypertensive subjects.
Methods
In the trial considerable care is taken to ascertain any fractures and to identify risk factors for fracture, such as falls, co-morbidity, drug treatment, smoking and drinking habits, levels of activity, biochemical abnormalities, cardiac irregularities, impaired cognitive function and symptoms of orthostatic hypotension.
Potential results
The trial is expected to provide 10,500 patient years of follow-up. Given a fracture rate of 40/1000 patient years and a 20% difference in fracture rate, the power of the sub study is 58% to detect this difference at the 5% level of significance. The corresponding power for a reduction of 25% is 78%.
Conclusion
The trial is well under way, expected to complete in 2009, and on target to detect, if present, the above differences in fracture rate.
doi:10.1186/1745-6215-7-33
PMCID: PMC1769508  PMID: 17177983

Results 1-7 (7)