Heparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity

Irie, Atsushi; Miki, Takami; Kubo, Hideo; Sekino-Suzuki, Naoko; Kasahara, Kohji; Sanai, Yutaka

doi:10.1016/j.bone.2007.04.190

Cited by 107 publications

(81 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…(34,35) It also has been shown that OPG HBD can interact with heparin and heparan sulfate and that cationic HBD is necessary for interaction with anionic proteoglycans. (25,36) Considering these previous findings, interaction of OPG with anionic proteoglycans in the Golgi apparatus might be a necessary step for RANKL transport to lysosomes. As for the DDHDs, it is reported that the DDHDs contribute to the dimer stability of OPG based on a comparison of OPG-CRD (¼ only CRD) protein and OPG-DHBD (¼ CRD þ DDHD) protein.…”

Section: Discussionmentioning

confidence: 84%

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Aoki

Honma

Kariya

et al. 2010

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

The amount of the receptor activator of NF-kB ligand (RANKL) on the osteoblastic cell surface is considered to determine the magnitude of the signal input to osteoclast precursors and the degree of osteoclastogenesis. Previously, we have shown that RANKL is localized predominantly in lysosomal organelles, but little is found on the osteoblastic cell surface, and consequently, the regulated subcellular trafficking of RANKL in osteoblastic cells is important for controlled osteoclastogenesis. Here we have examined the involvement of osteoprotegerin (OPG), which is currently recognized as a decoy receptor for RANKL, in the regulation of RANKL behavior. It was suggested that OPG already makes a complex with RANKL in the Golgi apparatus and that the complex formation is necessary for RANKL sorting to the secretory lysosomes. It was also shown that each structural domain of OPG is indispensable for exerting OPG function as a traffic regulator. In particular, the latter domains of OPG, whose physiologic functions have been unclear, were indicated to sort RANKL molecules to lysosomes from the Golgi apparatus. In addition, the overexpression of RANK-OPG chimeric protein, which retained OPG function as a decoy receptor but lost the function as a traffic regulator, inhibited endogenous OPG function as a traffic regulator selectively in osteoblastic cells and resulted in the upregulation of osteoclastogenic ability despite the increased number of decoy receptor molecules. Conclusively, OPG function as a traffic regulator for RANKL is crucial for regulating osteoclastogenesis at least as well as that as a decoy receptor. ß

show abstract

Section: Discussionmentioning

confidence: 84%

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Aoki

Honma

Kariya

et al. 2010

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…The effect of GAGs on osteoclastogenesis is controversial, as some studies showed a stimulation of osteoclastogenesis (Irie et al, 2007;Fuller et al, 1991) and others an inhibition (Shinmyouzu et al, 2007;Ariyoshi et al, 2008). It has been suggested that the mechanisms of action of GAGs on osteoclasts involved the inhibition of OPG, the decoy receptor for RANKL (Irie et al, 2007), or a direct interaction with RANKL leading to its inactivation (Shinmyouzu et al, 2007;Ariyoshi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that the mechanisms of action of GAGs on osteoclasts involved the inhibition of OPG, the decoy receptor for RANKL (Irie et al, 2007), or a direct interaction with RANKL leading to its inactivation (Shinmyouzu et al, 2007;Ariyoshi et al, 2008). It is worth noting that there are differences in the models used by these two teams.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Ariyoshi et al (2005) showed that hyaluronic acid, the most abundant GAG in mammalian tissues, enhances osteoclast formation and function, whereas in 2007, Chang et al described an opposite effect on osteoclastogenesis. Irie et al (2007) recently demonstrated that heparin in combination with 1,25(OH) 2 D3/PGE2 enhances the pit-forming activity of osteoclasts obtained from the coculture of mouse osteoblasts with bone marrow cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

“…In addition to CS-B, heparin was also reported to bind to RANKL and inhibit signal transduction from RANK-RANKL interaction 11) . On the other hand, another group reported that heparin binds specifically to osteoprotegerin (OPG) and not to RANKL 21) . We tried to investigate about the binding capacity of CS-E to RANKL, however, the strong and stable interactions were not seen (data not shown).…”

Section: Control Cs-c Cs-e Hepmentioning

confidence: 99%

Effect of chondroitin sulfate-E on the osteoclastic differentiation of RAW264 cells

Miyazaki

Miyauchi²,

Tawada³

et al. 2010

Dent. Mater. J.

View full text Add to dashboard Cite

The present study was designed to investigate whether chondroitin sulfate (CS)-E, a CS structural isomer variant, alter the differentiation of macrophage cell line RAW264 cells to osteoclast-like cells. CS-B, CS-E, low molecular weight CS-E, synthetic chondroitin polysulfate (CPS) and heparin significantly inhibited the formation of tartrate-resistant acid phosphatase-positive multinuclear cells and pit formation on calcium phosphate (CaP)-coated plates. CS-E pre-coated on the CaP plate also inhibited pit formation. Digestion of CS on the cell surface by chondroitinase showed no effect on the osteoclastic differentiation of RAW264 cells whereas inhibitory effect on the differentiation of osteoblastic cell line MC3T3-E1. On the other hand, exogenously added fluoresceinlabeled CS-E directory bound to fibronectin and RAW264 cells. These results suggest that CS-E structure on the surface of osteoblasts or bone matrix binds to cell adhesion molecule such as integrin on the pre-osteoclastic cells and inhibits the differentiation into osteoclasts. CS-E may have a potential in treating bone defect if combined with CaP materials.

show abstract

Heparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity

Cited by 107 publications

References 51 publications

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

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

Effect of chondroitin sulfate-E on the osteoclastic differentiation of RAW264 cells

Contact Info

Product

Resources

About