ArticleThe Journal of biological chemistry2016
Heparan Sulfate Regulates the Structure and Function of Osteoprotegerin in Osteoclastogenesis.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 38 citations in OpenAlex.
- Osteogenic Response of Dental Pulp Stem Cells (DPSCs) to an Alginate/Chitosan/Cannabidiol Hydrogel.Gels (Basel, Switzerland) · 2026Article
- An RBP-J-heparan sulfate-dependent gatekeeper directs macrophage fate between inflammatory regulation and osteoclastogenesis.bioRxiv : the preprint server for biology · 2026Article
- Proteoglycan Dynamics and Bone Quality: Molecular Regulation to Age-Related Fragility.Biomolecules · 2026Review
- The Role of Heparan Sulfate in Bone Repair and Regeneration.Calcified tissue international · 2025Review
- Biomaterial Cues for Regulation of Osteoclast Differentiation and Function in Bone Regeneration.Advanced therapeutics · 2025Article
- Control of tissue homeostasis by the extracellular matrix: Synthetic heparan sulfate as a promising therapeutic for periodontal health and bone regeneration.Periodontology 2000 · 2024Review
- Article
- Heparan sulfate promotes TRAIL-induced tumor cell apoptosis.bioRxiv : the preprint server for biology · 2023Article
- Glycobiology in osteoclast differentiation and function.Bone research · 2023Review
- Multiple Factors Involved in Bone Damage Caused by Chikungunya Virus Infection.International journal of molecular sciences · 2023Review
- Targeting heparan sulfate-protein interactions with oligosaccharides and monoclonal antibodies.Frontiers in molecular biosciences · 2023Review
- Mutation in the CCAL1 locus accounts for bidirectional process of human subchondral bone turnover and cartilage mineralization.Rheumatology (Oxford, England) · 2022Article
- Biochemical characterization of a disease-causing human osteoprotegerin variant.Scientific reports · 2022Article
- Angiotensin II Induces Aortic Rupture and Dissection in Osteoprotegerin-Deficient Mice.Journal of the American Heart Association · 2022Article
- Small leucine-rich proteoglycans in physiological and biomechanical function of bone.Matrix biology plus · 2021Review
- Effects of the TNFRSF11B Mutation Associated With Calcium Pyrophosphate Deposition Disease in Osteoclastogenesis in a Murine Model.Arthritis & rheumatology (Hoboken, N.J.) · 2021Article
- The heparan sulfate proteoglycan Syndecan-1 influences local bone cell communication via the RANKL/OPG axis.Scientific reports · 2020Article
- Article
- Antiresorptive activity of osteoprotegerin requires an intact heparan sulfate-binding site.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Osteoprotegerin (OPG), a decoy receptor secreted by osteoblasts, is a major negative regulator of bone resorption. It functions by neutralizing the receptor activator of nuclear factor κB ligand (RANKL), which plays a central role in promoting osteoclastogenesis. OPG is known to be a high-affinity heparan sulfate (HS)-binding protein. Presumably, HS could regulate the function of OPG and affect how it inhibits RANKL. However, the molecular detail of HS-OPG interaction remains poorly understood, which hinders our understanding of how HS functions in osteoclastogenesis. Here we report mapping of the HS-binding site of OPG. The HS-binding site, identified by mutagenesis study, consists of eight basic residues that are located mostly at the junction of the second death domain and the C-terminal domain. We further show that heparin-derived dodecasaccharide is able to induce dimerization of OPG monomers with a stoichiometry of 1:1. Small-angle X-ray scattering analysis revealed that upon binding of HS, OPG undergoes a dramatic conformational change, resulting in a more compact and less flexible structure. Importantly, we present here three lines of evidence that HS, OPG, and RANKL form a stable ternary complex. Using a HS binding-deficient OPG mutant, we further show that in an osteoblast/bone marrow macrophage co-culture system, immobilization of OPG by HS at the osteoblast cell surface substantially lowers the inhibitory threshold of OPG toward RANKL. These discoveries strongly suggest that HS plays an active role in regulating OPG-RANKL interaction and osteoclastogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.