Contribution of biomimetic collagen-ligand interaction to intrafibrillar mineralization

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Abstract

Collagen-bound nucleation inhibitor ameliorates mineralization via caching of prenucleation clusters.

Abstract

Contemporary models of intrafibrillar mineralization mechanisms are established using collagen fibrils as templates without considering the contribution from collagen-bound apatite nucleation inhibitors. However, collagen matrices destined for mineralization in vertebrates contain bound matrix proteins for intrafibrillar mineralization. Negatively charged, high–molecular weight polycarboxylic acid is cross-linked to reconstituted collagen to create a model for examining the contribution of collagen-ligand interaction to intrafibrillar mineralization. Cryogenic electron microscopy and molecular dynamics simulation show that, after cross-linking to collagen, the bound polyelectrolyte caches prenucleation cluster singlets into chain-like aggregates along the fibrillar surface to increase the pool of mineralization precursors available for intrafibrillar mineralization. Higher-quality mineralized scaffolds with better biomechanical properties are achieved compared with mineralization of unmodified scaffolds in polyelectrolyte-stabilized mineralization solution. Collagen-ligand interaction provides insights on the genesis of heterogeneously mineralized tissues and the potential causes of ectopic calcification in nonmineralized body tissues.

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Most cited references 35

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New insights into the biology of osteocalcin.

Meredith L Zoch, Thomas L Clemens, Ryan C Riddle (2016)

Osteocalcin is among the most abundant proteins in bone and is produced exclusively by osteoblasts. Initially believed to be an inhibitor of bone mineralization, recent studies suggest a broader role for osteocalcin that extends to the regulation of whole body metabolism, reproduction, and cognition. Circulating undercarboxylated osteocalcin, which is regulated by insulin, acts in a feed-forward loop to increase β-cell proliferation as well as insulin production and secretion, while skeletal muscle and adipose tissue respond to osteocalcin by increasing their sensitivity to insulin. Osteocalcin also acts in the brain to increase neurotransmitter production and in the testes to stimulate testosterone production. At least one putative receptor for osteocalcin, Gprc6a, is expressed by adipose, skeletal muscle, and the Leydig cells of the testes and appears to mediate osteocalcin's effects in these tissues. In this review, we summarize these new discoveries, which suggest that the ability of osteocalcin to function both locally in bone and as a hormone depends on a novel post-translational mechanism that alters osteocalcin's affinity for the bone matrix and bioavailability. This article is part of a Special Issue entitled Bone and diabetes.

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The role of prenucleation clusters in surface-induced calcium phosphate crystallization.

J. Will, P Frederik, A Dey … (2010)

Unravelling the processes of calcium phosphate formation is important in our understanding of both bone and tooth formation, and also of pathological mineralization, for example in cardiovascular disease. Serum is a metastable solution from which calcium phosphate precipitates in the presence of calcifiable templates such as collagen, elastin and cell debris. A pathological deficiency of inhibitors leads to the uncontrolled deposition of calcium phosphate. In bone and teeth the formation of apatite crystals is preceded by an amorphous calcium phosphate (ACP) precursor phase. ACP formation is thought to proceed through prenucleation clusters--stable clusters that are present in solution already before nucleation--as was recently demonstrated for CaCO(3) (refs 15,16). However, the role of such nanometre-sized clusters as building blocks for ACP has been debated for many years. Here we demonstrate that the surface-induced formation of apatite from simulated body fluid starts with the aggregation of prenucleation clusters leading to the nucleation of ACP before the development of oriented apatite crystals.

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Osteonectin, a bone-specific protein linking mineral to collagen.

J Termine, H K Kleinman, S Whitson … (1981)

Osteonectin is a 32,000 dalton bone-specific protein that binds selectively to both hydroxyapatite and collagen. When osteonectin is bound to insolubilized type I collagen, the resultant complex binds synthetic apatite crystals and free calcium ions. The osteonectin-collagen complexes also nucleate mineral phase deposition from metastable balanced salt solutions, Antibodies to osteonectin cross-react with bone and, to a lesser extent, dentin, but not with other tissues. The protein is localized to mineralized bone trabeculae and occurs at higher levels in the matrix than in the cells of bone. These studies suggest that osteonectin is a tissue-specific protein, linking the bone mineral and collagen phases, perhaps initiating active mineralization in normal skeletal tissue.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: March 2019

Publication date (Electronic): 29 March 2019

Volume: 5

Issue: 3

Electronic Location Identifier: eaav9075

Affiliations

[1 ]State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’ an, Shaanxi, PR China.

[2 ]Department of Biological Structure, School of Medicine, University of Washington, Seattle, WA, USA.

[3 ]Department of Applied Physics, Xi'an Jiaotong University, Xi’an, Shaanxi, PR China.

[4 ]Frontier Institute of Science and Technology and State Key Laboratory for Mechanical Behavior of Materials, Xi’an Jiaotong University, Xi’an, Shaanxi, PR China.

[5 ]Department of Materials Science & Engineering, University of Washington, Seattle, WA, USA.

[6 ]Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.

[7 ]College of Dental Medicine, Augusta University, Augusta, GA, USA.

Author notes

[*]

These authors contributed equally to this work.

[† ]Corresponding author. Email: jhchen@ 123456fmmu.edu.cn (J.H.C.); ftay@ 123456augusta.edu (F.R.T.); niulina831013@ 123456126.com (L.N.N.)

Author information

Q. Song http://orcid.org/0000-0002-0999-6022

L. Tonggu http://orcid.org/0000-0002-0033-556X

L. G. Wang http://orcid.org/0000-0002-7095-5983

L. Zhang http://orcid.org/0000-0002-4880-824X

J. H. Bian http://orcid.org/0000-0002-8294-7761

D. X. Hao http://orcid.org/0000-0002-0659-7210

J. H. Chen http://orcid.org/0000-0002-1151-0693

F. R. Tay http://orcid.org/0000-0002-4704-919X

L. N. Niu http://orcid.org/0000-0002-6653-0819

Article

Publisher ID: aav9075

DOI: 10.1126/sciadv.aav9075

PMC ID: 6459768

PubMed ID: 30989106

SO-VID: 20cd8ceb-f58c-454f-b5c0-545d13de88db

Copyright © Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 01 November 2018

Date accepted : 06 February 2019

Funding

Funded by: National Nature Science Foundation of China;

Award ID: 81722015

Funded by: National Nature Science Foundation of China;

Award ID: 81870805

Funded by: National Nature Science Foundation of China;

Award ID: 81720108011

Funded by: National Nature Science Foundation of China;

Award ID: 81671012

Funded by: Changjiang Scholars and Innovative Research Team in University;

Award ID: IRT13051

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Copyeditor Fritzie Benzon

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Contribution of biomimetic collagen-ligand interaction to intrafibrillar mineralization

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Most cited references 35

New insights into the biology of osteocalcin.

The role of prenucleation clusters in surface-induced calcium phosphate crystallization.

Osteonectin, a bone-specific protein linking mineral to collagen.

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