Osteoblastic heparan sulfate regulates osteoprotegerin function and bone mass

Nozawa, Satoshi; Inubushi, Toshihiro; Irie, Fumitoshi; Takigami, Iori; Matsumoto, Kazu; Shimizu, Katsuji; Akiyama, Haruhiko; Yamaguchi, Yu

doi:10.1172/jci.insight.89624

Cited by 25 publications

(23 citation statements)

References 66 publications

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“…Moreover, our data show that Wnt1 has an OPG‐independent direct juxtacrine effect in suppressing osteoclastogenesis. Interestingly, recent studies indicate that binding of OPG on the osteoblast cell surface via heparin sulfate does greatly enhance the ability of OPG to inhibit RANKL and subsequently osteoclastogenesis . Thus, based on our data we conclude that membrane‐bound Wnt1 and OPG regulate osteoclastogenesis in concert in a juxtacrine manner.…”

Section: Discussionsupporting

confidence: 70%

Mesenchymal Cell-Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation

Wang

Tarkkonen

Nieminen-Pihala

et al. 2019

Journal of Bone and Mineral Research

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Human genetic evidence demonstrates that WNT1 mutations cause osteogenesis imperfecta (OI) and early‐onset osteoporosis, implicating WNT1 as a major regulator of bone metabolism. However, its main cellular source and mechanisms of action in bone remain elusive. We generated global and limb bud mesenchymal cell–targeted deletion of Wnt1 in mice. Heterozygous deletion of Wnt1 resulted in mild trabecular osteopenia due to decreased osteoblast function. Targeted deletion of Wnt1 in mesenchymal progenitors led to spontaneous fractures due to impaired osteoblast function and increased bone resorption, mimicking the severe OI phenotype in humans with homozygous WNT1 mutations. Importantly, we showed for the first time that Wnt1 signals strictly in a juxtacrine manner to induce osteoblast differentiation and to suppress osteoclastogenesis, in part via canonical Wnt signaling. In conclusion, mesenchymal cell‐derived Wnt1, acting in short range, is an essential regulator of bone homeostasis and an intriguing target for therapeutic interventions for bone diseases. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 70%

Mesenchymal Cell-Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation

Wang

Tarkkonen

Nieminen-Pihala

et al. 2019

Journal of Bone and Mineral Research

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“…Despite extensive structural studies, our understanding of the working mechanics of OPG at the intact protein level remains rudimentary due to a lack of structural insight on the C-terminal half of the molecule. Recently, we and others have shown that osteoblast HS plays an essential role in immobilizing OPG on the cell surface and is required for OPG to inhibit RANKL properly by binding to the DD2 and tail domains (5,32). Furthermore, we have obtained strong evidence that HSbinding converts OPG to a more compact and less flexible conformation, and that HS-OPG-RANKL form a stable ternary complex.…”

Section: Discussionmentioning

confidence: 54%

“…In this system, primary osteoblasts are stimulated with vitamin D 3 and dexamethasone to induce expression of macrophage colony-stimulating factor and membrane-bound RANKL, which drives differentiation of co-cultured bone marrow macrophages into osteoclasts (2). Adding recombinant OPG into the system should dose-dependently inhibit RANKL and thus the extent of osteoclast differentiation (5,32). As expected, L254A,F385A and W257A,M388A OPG SH both showed reduced potency in inhibiting osteoclastogenesis compared with WT OPG SH .…”

Section: Hydrophobic Residues Are Required For Optimal Activity Of Opmentioning

confidence: 66%

“…Fig. 4, peptide [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] was found to be quite dynamic, with high deuteration levels that were insensitive to addition of HS and/or RANKL. This behavior is consistent with the view that CRD1 is not involved in HS or RANKL binding, both in the case of OPG SH and OPG 2 SS (3, 5, 7).…”

Section: Overall Hdx Pattern Of Opgmentioning

confidence: 99%

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Dimerization interface of osteoprotegerin revealed by hydrogen–deuterium exchange mass spectrometry

Xiao

Larocque

et al. 2018

Journal of Biological Chemistry

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Previous structural studies of osteoprotegerin (OPG), a crucial negative regulator of bone remodeling and osteoclastogenesis, were mostly limited to the N-terminal ligand-binding domains. It is now known that the three C-terminal domains of OPG also play essential roles in its function by mediating OPG dimerization, OPG-heparan sulfate (HS) interactions, and formation of the OPG-HS-receptor activator of nuclear factor B ligand (RANKL) ternary complex. Employing hydrogendeuterium exchange MS methods, here we investigated the structure of full-length OPG in complex with HS or RANKL in solution. Our data revealed two noteworthy aspects of the OPG structure. First, we found that the interconnection between the N-and C-terminal domains is much more rigid than previously thought, possibly because of hydrophobic interactions between the fourth cysteine-rich domain and the first death domain. Second, we observed that two hydrophobic clusters located in two separate C-terminal domains directly contribute to OPG dimerization, likely by forming a hydrophobic dimerization interface. Aided by site-directed mutagenesis, we further demonstrated that an intact dimerization interface is essential for the biological activity of OPG. Our study represents an important step toward deciphering the structure-function relationship of the full-length OPG protein.

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“…This pathway is based on the increased differentiation of osteoclasts through the binding of the RANKL ligand to its membrane receptor (RANK) on mononuclear osteoclast precursors. This increased differentiation of osteoclasts by RANKL is inhibited by the OPG that is produced by osteoblasts (3).…”

Section: Introductionmentioning

confidence: 98%

Investigation of the presence of G354A (Cys87Tyr) mutation in osteoprotegerin gene in women with osteoporosis in Chaharmahal and Bakhtiari province

Mousavi

Dehghan

Pourahmad

2019

J Shahrekord Univ Med Sci

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Background and aims: Osteoprotegerin (OPG) is a competitive inhibitor of the differentiation and activity of osteoclasts, which inhibits the final stages of osteoclast formation and induces its apoptosis. In addition, OPG is considered as one of the most important candidate genes in the pathogenesis of bone diseases such as osteoporosis and idiopathic hyperphosphatasia. The G354A (Cys87Tyr) mutation in the OPG gene leads to idiopathic hyperphosphatasia. This mutation is probably related to osteoporosis. The purpose of this study was to investigate the presence of G354A (Cys87Tyr) in women with osteoporosis in Chaharmahal and Bakhtiari province. Methods: In this descriptive-analytical study, the bone mineral density (BMD) of the femoral neck and lumbar spine of women referring to Shahrekord bone densitometry centers was measured by the X-ray absorptiometry technique in 2013-2014. Based on T-scores, people with osteoporosis were identified and 70 patients were enrolled in the study after receiving their consent. Finally, DNA was extracted from blood samples, amplified by polymerase chain reaction (PCR) technique, and sequenced by DNA sequencing method. Results: After DNA extraction from the blood, the quality and quantity were determined by gel electrophoresis and spectrophotometry, respectively. Then, the gene was amplified by the PCR method and the product was detected by gel electrophoresis, followed by sequencing the samples to investigate the presence of the mutation. Eventually, genotypes associated with Cys87Tyr mutation were not observed in the studied population. Conclusion: In the present study, the G354A (Cys87Tyr) mutation associated with idiopathic hyperphosphatasia was not found in women with osteoporosis.

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Osteoblastic heparan sulfate regulates osteoprotegerin function and bone mass

Cited by 25 publications

References 66 publications

Mesenchymal Cell-Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation

Mesenchymal Cell-Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation

Dimerization interface of osteoprotegerin revealed by hydrogen–deuterium exchange mass spectrometry

Investigation of the presence of G354A (Cys87Tyr) mutation in osteoprotegerin gene in women with osteoporosis in Chaharmahal and Bakhtiari province

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