The effects of heparin and low molecular weight heparins on bone

Rajgopal, Raghav; Bear, Mackenzie; Butcher, Martin; Shaughnessy, Stephen G.

doi:10.1016/j.thromres.2006.10.025

Cited by 124 publications

(73 citation statements)

References 29 publications

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“…Furthermore, we demonstrated the importance of the length and the sulfation of the GAGs in their inhibitory effect. Such structural significance has been already shown in other biological models (Hallak et al, 2000;McDonnell et al, 2004;Rajgopal et al, 2008). The influence of GAG length on osteoclastogenesis has been also suggested by in vivo study.…”

Section: Discussionsupporting

confidence: 58%

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Glycosaminoglycans inhibit the adherence and the spreading of osteoclasts and their precursors: Role in osteoclastogenesis and bone resorption

Baud’huin

Ruiz-Velasco

Jégo

et al. 2011

European Journal of Cell Biology

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The bone microenvironment (e.g. glycosaminoglycans (GAGs), growth factors) plays a major role in bone resoption, especially in the formation of osteoclast which differentiate from the hematopoietic lineage in the presence of RANKL. Previous studies revealed that GAGs may influence osteoclastogenesis, but data are very controversial, some studies showing an inhibitory effect of GAGs on osteoclastic differentiation whereas others demonstrated a stimulatory effect. To clarify their activities, we investigated the effect of 5 families of GAGs in three different models of human/mouse osteoclastogenesis. The present data revealed that heparin inhibited osteoclastogenesis in these 3 models, which was confirmed by a decrease in mRNA expression of osteoclastic markers and by an inhibition of the bone resorption capacity. We also demonstrated in RAW 264.7 cells that other families of GAGs different from heparin inhibited RANKL-induced osteoclastogenesis, and that this inhibition was dependent on the length and the level of sulfation of GAGs. In the present work, heparin did not bind to RANKL and did not modulate RANKL signaling. Heparin acted at 2 distinct steps of osteoclastogenesis from human CD14 + cells: first, heparin strongly decreased the adherence of osteoclast precursors, and secondly inhibited osteoclasts to spread and to be active. Furthermore, the second action of heparin was reversible as the removal of heparin at the end of the culture time allowed the condensed cells to spread out and showed the formation of morphological active osteoclasts. The present work clearly evidences that GAGs inhibit osteoclastogenesis in vitro and strengthens the therapeutic interest of defined GAGs in osteolytic diseases.

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Section: Discussionsupporting

confidence: 58%

“…Indeed, in contrast to unfractioned heparin which seems to decrease bone formation and increase bone resorption, low molecular weight heparins cause less bone loss because they only decrease bone formation and have no effect on bone resorption (Rajgopal et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Glycosaminoglycans inhibit the adherence and the spreading of osteoclasts and their precursors: Role in osteoclastogenesis and bone resorption

Baud’huin

Ruiz-Velasco

Jégo

et al. 2011

European Journal of Cell Biology

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“…LMW heparin-like compounds appear to cause less adverse effects on bone than in unfractionated heparin (reviewed in ref. 35). Size and sulfation of the heterogeneous group of HLGAGs are suggested to be the major determinants of their ability to promote bone resorption (34) and suppress bone formation (30).…”

Section: Discussionmentioning

confidence: 99%

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Pollari

Käkönen

Mohammad

et al. 2012

Molecular Cancer Research

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TGF-b regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-b is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-Osulfotransferase 2 (HS6ST2) as a critical gene for TGF-b-induced IL-11 production in highly bone metastatic MDA-MB-231(SA) breast cancer cells. HS6ST2 attaches sulfate groups to glucosamine residues in heparan sulfate glycosaminoglycans. We subsequently showed how heparin and a high-molecular-weight Escherichia coli K5-derived heparin-like polysaccharide (K5-NSOS) inhibited TGF-b-induced IL-11 production in MDA-MB-231 (SA) cells. In addition, K5-NSOS inhibited bone resorption activity of human osteoclasts in vitro. We evaluated the therapeutic potential of K5-NSOS and fragmin in a mouse model of breast cancer bone metastasis. MDA-MB-231 (SA) cells were inoculated into the left cardiac ventricle of athymic nude mice which were treated with fragmin, K5-NSOS, or vehicle once a day for four weeks. Both heparin-like glycosaminoglycans inhibited weight reduction, decreased osteolytic lesion area, and reduced tumor burden in bone. In conclusion, our data imply novel mechanisms involved in TGF-b induction and support the critical role of heparan sulfate glycosaminoglycans in cancer metastasis as well as indicate that K5-NSOS is a potential antimetastatic and antiresorptive agent for cancer therapy. This study illustrates the potential to translate in vitro siRNA screening results toward in vivo therapeutic concepts. Mol Cancer Res; 10(5); 597-604. Ó2012 AACR.

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“…Using 125 I-labelled heparin, it has been demonstrated that it accumulates and remains in bone long after stopping the treatment [11]. It induces bone resorption by increasing the number and activity of osteoclasts (OC), probably by inhibiting the expression of osteoprotegerin (OPG) [12]. In parallel, heparin reduces bone formation by decreasing the number and activity of osteoblasts (OB) [12].…”

Section: Introductionmentioning

confidence: 99%

“…It induces bone resorption by increasing the number and activity of osteoclasts (OC), probably by inhibiting the expression of osteoprotegerin (OPG) [12]. In parallel, heparin reduces bone formation by decreasing the number and activity of osteoblasts (OB) [12]. However, the precise mechanism of heparin's effect on bone remodelling remains undetermined.…”

Section: Introductionmentioning

confidence: 99%

Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity

Brkljačić

Pauk

Erjavec

et al. 2013

International Orthopaedics (SICOT)

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Purpose The purpose of this study was to explore the effect of heparin on bone morphogenetic protein 6 (BMP6) osteogenic activity. Methods Western blot analysis was used to confirm the binding of BMP6 to heparin and to observe its effect on BMP6 signaling in C2C12-BRE-Luc myoblasts. Real-time RT-PCR was performed for the expression analysis of alkaline phosphatase (ALP) and osteocalcin (OC) in C2C12 myoblasts treated with BMP6 and heparin for 72 hours. Rat ectopic bone formation assay was performed to explore the effect of heparin on BMP6 osteogenic activity. Two weeks following implantation the implants were analysed morphologically and histologically. A mouse osteoporotic model was used to test the ability of BMP6 to improve the bone quality in vivo in the presence of heparin, followed by DEXA and μCT analyses. Blood coagulation was tested in rats previously treated with BMP6. Results BMP6 specifically bound to heparin and induced Smad1/5/8 phosphorylation which was inhibited by heparin. After 48 and 72 hours of treatment, heparin inhibited BMP6-induced ALP and OC expression in C2C12 cells. Heparin dose dependently inhibited BMP6-induced new bone and cartilage formation in the rat ectopic bone formation assay, while in osteoporotic mice heparin inhibited the BMP6 potential to improve the bone quality as evidenced by decreased bone mineral density and trabecular bone parameters. Interestingly, BMP6 prevented the effect of heparin on the blood coagulation parameters. Conclusion The interaction of BMP6 with heparin might contribute to the heparin-induced osteoporosis and blood coagulation.

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The effects of heparin and low molecular weight heparins on bone

Cited by 124 publications

References 29 publications

Glycosaminoglycans inhibit the adherence and the spreading of osteoclasts and their precursors: Role in osteoclastogenesis and bone resorption

Glycosaminoglycans inhibit the adherence and the spreading of osteoclasts and their precursors: Role in osteoclastogenesis and bone resorption

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity

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