Search PubMed⌕ Search

Biomedical subjects

Martine Cohen-Solal

Publications and source records attributed to Martine Cohen-Solal.

9 recordsLinked to original sources
PubMed2005

Cannabinoid receptor type 2 gene is associated with human osteoporosis.

Osteoporosis is one of the most common degenerative diseases. It is characterized by reduced bone mineral density (BMD) with an increased risk for bone fractures. There is a substantial genetic contribution to BMD, although the genetic factors involved in the pathogenesis of human osteoporosis are largely unknown. Mice with a targeted deletion of either the cannabinoid receptor type 1 (Cnr1) or type 2 (Cnr2) gene show an alteration of bone mass, and pharmacological modification of both receptors can regulate osteoclast activity and BMD. We therefore analyzed both genes in a systematic genetic association study in a human sample of postmenopausal osteoporosis patients and matched female controls. We found a significant association of single polymorphisms (P = 0.0014) and haplotypes (P = 0.0001) encompassing the CNR2 gene on human chromosome 1p36, whereas we found no convincing association for CNR1. These results demonstrate a role for the peripherally expressed CB2 receptor in the etiology of osteoporosis and provide an interesting novel therapeutical target for this severe and common disease.

Animals↗
PubMed2004

Role for osteoprotegerin in rheumatoid inflammation.

Osteoprotegerin (OPG), a member of the TNF-receptor family expressed by osteoblasts, has documented effects on the regulation of bone metabolism. OPG inhibits bone resorption and binds with strong affinity to its ligand RANKL, thereby preventing RANKL from binding to its receptor RANK. This system is regulated by calcium-modifying hormones. OPG may also be pivotal in modulating the immune system. RANKL-deficient mice exhibit both severe immunological abnormalities and osteopetrosis, and activated T cells express RANKL mRNA. RANKL secretion by activated T cells may induce osteoclastogenesis via a mechanism enhanced by several cytokines (TNF-alpha, IL-1, and IL-17) that promote both inflammation and bone resorption. Conversely, this mechanism is inhibited by OPG, IL-4, and IL-10, which have antiinflammatory effects and inhibit osteoclast formation. Activated T cells in the rheumatoid synovium express RANKL. Synoviocytes can differentiate to osteoclast-like cells under specific conditions, particularly when they are cultured with M-CSF and RANKL. Thus, the bony erosions seen in RA may result from RANKL/RANK system activation by activated T cells. This raises the possibility that OPG therapy to block this mechanism might prove beneficial in patients with RA.

Animals↗
PubMed2004

Interleukin-4 cellular gene therapy and osteoprotegerin decrease inflammation-associated bone resorption in collagen-induced arthritis.

To evaluate the respective action of IL-4, an anti-inflammatory cytokine, and OPG, an inhibitor of bone resorption, on the inflammatory process and the associated bone resorption in collagen-induced arthritis (CIA). After CIA induction, DBA/1 mice were treated with OPG or with IL-4 DBA/1 transfected fibroblasts or both OPG + IL-4. CIA significantly improved in IL-4 groups. OPG had no effect on arthritis clinical scores but histologic scores were reduced in OPG, IL-4, and OPG + IL-4 groups vs. nontreated CIA mice. OPG increased significantly BMD and decreased by 45% D-pyridinolin levels. Moreover association of IL-4 and OPG exerted an additive effect of BMD and resorption marker (-68%). Production of IFN-gamma in the supernatants of spleen cells was reduced in IL-4 treated mice. OPG had a moderate effect on IFN-gamma, but potentiated the inhibitory effect of IL-4. OPG and IL-4 prevent bone loss in CIA-mice model and could have additive effects on IFN-gamma secretion.

Animals↗
PubMed2003

Bone mineral density, biochemical markers and skeletal fractures in haemodialysis patients.

BACKGROUND: End-stage renal disease is often associated with altered bone metabolism. METHODS: In order to investigate the determinant factors of bone mineral density (BMD) and the risk factors of fractures, we studied 70 patients; 26 women (23 post-menopausal) and 44 men, (mean+/-SD) aged 60.5+/-14.3 years, treated by standard haemodialysis (HD) for 6.4+/-6.8 years. Main circulating bone biochemical markers were assessed and BMD was measured with a Lunar DPX densitometer at five sites. BMD results are expressed as a function of age and gender (Z-score). RESULTS: Mean Z-score was markedly decreased at the mid-radius (-2.75+/-1.23) whereas it was normal at the femoral neck (-0.42+/-1.13) and lumbar spine (0.02+/-2.13), and total body (-0.62+/-1.53). Time on HD was negatively correlated to the Z-score at the mid-radius and total body but not at the other sites. Serum intact parathyroid hormone (iPTH), whole PTH or cyclase activating PTH (CAP) and bone-specific alkaline phosphatase concentrations were negatively correlated with Z-scores at all sites. Twenty-one out of 70 patients had sustained a total of 27 fractures since the beginning of dialysis therapy (seven ribs, seven ankles, six vertebrae, three humerus, two wrists and two hips). They had a total body Z-score significantly lower than that of patients without fractures, -1.34+/-1.54 vs -0.37+/-1.46, respectively (P<0.031); however, their Z-scores at the other sites were not different. They were on HD for longer time, 10.4+/-9.5 vs 5.0+/-5.1, respectively (P<0.003), and the relative risk of skeletal fractures was 6.4 times greater after 10 years of HD. The seven patients with rib fractures had a decreased Z-score at most of the sites but not at the mid-radius. Rib fractures but no other fractures were associated with markedly decreased body weight, fat mass and serum leptin levels. CONCLUSIONS: In conclusion, the Z-score at the mid-radius was decreased in HD patients and correlated with high serum PTH but not with fractures. Bone fractures were associated with the time passed on HD and with a low total body Z-score. Rib fractures were frequent and associated with a poor nutritional state.

Adult↗
PubMed2002

Integrin alpha(v)beta3 expression confers on tumor cells a greater propensity to metastasize to bone.

The reasons why tumor cells metastasize to bone remain obscure. There is some evidence to support the theory that integrins (acting as cell surface adhesion receptors) play a role in mediating metastasis in certain organs. Here, we report that overexpression of a functionally active integrin alpha(v)b3 in Chinese hamster ovary (CHO) tumor cells drastically increased the incidence, number, and area of bone metastases in nude mice compared with those observed in mock-transfected CHO cells (CHO dhfr+) or in CHO cells expressing a functionally inactive integrin alpha(v)b3 (CHO beta3Delta744). Moreover, a breast cancer cell line (B02) established from bone metastases caused by MDA-MB-231 cells constitutively overexpressed integrin alpha(v)b3, whereas the cell surface expression level of other integrins remained unchanged. In vivo, the extent of bone metastases in B02-bearing mice was significantly increased compared with that of MDA-MB-231-bearing mice. In vitro, B02 cells and CHO cells expressing a functionally active integrin alpha(v)b3 exhibited substantially increased invasion of and adhesion to mineralized bone, bone sialoprotein, and collagen compared with those found with MDA-MB-231, CHO dhfr+, and CHO beta3Delta744 cells, respectively. Overall, our findings suggest that integrin alpha(v)b3 expression in tumor cells accelerates the development of osteolytic lesions, presumably through increased invasion of and adhesion to bone.

Animals↗
PubMed2002

Strontium overload and toxicity: impact on renal osteodystrophy.

Although the prevalence of aluminium-related bone diseases has declined, osteomalacia still persists at a low prevalence. The redistribution of bone disease prevalence corresponds to evolving regimens in the treatment of renal disease. Studies have demonstrated an association between the accumulation of strontium in bone and the presence of osteomalacia. The uptake of strontium has been shown to be dose-dependent, with distribution mainly in newly formed compact and cancellous bone. Animal studies demonstrated that high doses of strontium induced alterations of mineralization and, in a rat model of chronic renal failure, high strontium doses induced mineralization defects, with a corresponding 160-fold accumulation of strontium in bone. Studies indicated that the accumulation of metals in bone might be synergistic. Aluminium bone content was shown to be higher when both aluminium and strontium were administered compared with when only strontium was given. Studies in dialysis patients demonstrated that strontium levels and strontium/calcium ratios were elevated in the bone of osteomalacia patients compared with other types of renal osteodystrophy. In certain dialysis centres of developing countries, high strontium levels present in dialysis fluids correlated with strontium serum content. At these centres, the use of acetate-based concentrates may have been the source of strontium-contaminated dialysis fluids. In a recent study of bone biopsies taken from patients of French dialysis centres, strontium content was increased in bone of osteomalacic patients compared with other bone diseases and with controls. Several other trace elements have been found to accumulate in the bone of uraemic patients, with significant concern regarding associated pathology. Environmental and medical exposure to such trace metals should be evaluated to establish toxic thresholds and to eliminate the possibility of associated renal osteopathies.

Animals↗
PubMedDate not supplied

[Bone remodeling].

The physiological maintenance of bone mass is ensured by bone tissue renewal, allowing old bone tissue to be replaced by an equivalent mass of bone matrix. After mechanical or hormonal stress activation, a phase of resorption by osteoclasts occurs, followed by a phase of bone formation by osteoblasts. Among the multiple factors involved in osteoblastic differentiation are the following: Cbfa1 (transcription factor); low density lipoprotein receptor-related protein-5 (LRP-5), a membrane lipoprotein receptor and protein Wnt co-receptor, which plays an important role during development. It is possible that osteoblastic proliferation and differentiation are regulated by distinct pathways. Osteoclastic differentiation is also regulated by numerous factors: osteoprotegerin (OPG); RANK-L (receptor activator of nuclear factor kappa B ligand, a transmembrane protein related to tumour necrosis factor [TNF], the binding of which to its RANK receptor induces osteoclastic differentiation); and soluble TNF receptors. Local regulation of the OPG/RANK-L ratio could explain postmenopausal loss of bone mass. OPG could play a major role in myeloma and Paget disease. Osteolysis together with bone metastasis could also be related to the local production of RANK-L. OPG decreases osteolysis and offers an interesting therapeutic perspective for the treatment of osteoporosis and other diseases associated with bone hyper-resorption.

Bone Remodeling↗