Elsevier

Carbohydrate Polymers

Volume 294, 15 October 2022, 119773
Carbohydrate Polymers

Review
Regulation of biomineralization by proteoglycans: From mechanisms to application

https://doi.org/10.1016/j.carbpol.2022.119773Get rights and content

Highlights

  • The mechanism involved in the biomineralization mediated by proteoglycans is reviewed.

  • The important role of proteoglycans in matrix-mediated bone formation is discussed.

  • Proteoglycans in pathological mineralization and corresponding intervention targets are summarized.

  • Proteoglycan-based biomaterials which bring a promising prospect for bone tissue regeneration are expected.

Abstract

Proteoglycans consist of core proteins and one or more covalently-linked glycosaminoglycan chains. They are structurally complex and heterogeneous. Proteoglycans bind to cell surface receptors, cytokines, growth factors and have strong affinity for collagen fibrils. Together with their complex spatial structures and different charge densities, proteoglycans are directly or indirectly involved in biomineralization. The present review focused on the potential mechanisms of proteoglycans-mediated biomineralization. Topics covered include the ability of proteoglycans to influence the proliferation and differentiation of odontoblasts and osteoblasts through complex signaling pathways, as well as regulate the aggregation of collagen fibrils and mineral deposition. The functions of proteoglycans in mineralization regulation and biomimetic properties render them important components in bone tissue engineering. Hence, the integrated impact of proteoglycans on bone formation was also succinctly deliberated. The potential of proteoglycans to function therapeutic targets for relieving the symptoms of ectopic mineralization and mineralization defects was also comprehensively addressed.

Introduction

Biomineralization refers mineral deposition in biological systems. This is a concerted effort that involves the participation of organic templates, mineralization inhibitors and amorphous mineral precursors. Biomineralization is an exquisite example of naturally-occurring self-assembly of nanomaterials. Collagen fibrils in the extracellular matrix (ECM) act as templates for biomineralization. Although the ECM of bone consists primarily of collagen, non-collagenous proteins are actively engaged in the activation and inhibition of biomineralization (Behrens & Baeuerlein, 2007).

Non-collagenous proteins comprise 180–200 different molecules and account for 5–10 % of the ECM. They are divided into four categories: proteoglycans, glycoproteins, γ-carboxyglutamate-containing proteins and serum-related proteins. These entities perform structural, signaling or mechanical roles in the tissues in which they are located (Bailey et al., 2017; Licini et al., 2019; Oya et al., 2017). Proteoglycans as macromolecular complexes that perform the aforementioned three functions in mineralized tissues. They are characterized by covalent binding of long-chain polysaccharides known as glycosaminoglycans (GAGs) with core protein molecules. Subclasses of proteoglycans are characterized by the structure of their core proteins and the properties of their GAG attachments. Although other types of molecules may also be sulfated, the sulfate content of proteoglycans within any organic matrix exceeds 95 % (Lamoureux et al., 2007). The content and position of sulfate are extremely variable in sulfated GAGs (Shi et al., 2014), depending on the tissue/cellular/metabolic constraints. This diversity ensures structural variability of these polysaccharides and bestows functional diversity (Lamoureux et al., 2007).

Although proteoglycans are not as abundant as structural proteins such as collagen, their significance in biomineralization cannot be underestimated. This is exemplified by the identification of abnormal phenotypes that are caused by proteoglycan mutations (Kemp et al., 2017). Proteoglycans are involved in structural organization of the ECM by interacting with multiple matrix components and acting as cross-linkers. They exhibit a broad array of functions that include mediation of carbonated apatite deposition, control of cell proliferation through regulation of growth factor activity, matrix organization and bone formation.

Biomineralization produces both positive and negative results depending on changes in the micro-environment and cell functioning. Physiological mineralization is limited to bones, teeth and the hypertrophic area of growth plate cartilage. Pathological mineralization may be found in any tissue and is referred to “ectopic calcification” (De Maré et al., 2020). The high incidence of diseases associated with ectopic calcification or bone mineralization defects pinnacles the importance of understanding the molecular mechanisms of ECM mineralization. Abnormal or ectopic expression of osteogenic cells also plays a significant role in pathological processes such as atherosclerosis, osteoarthritis and genetic diseases in which the inactivation of specific genes results in local pathological mineralization (Hahn et al., 2015; Reiss et al., 2018; Sherwood, 2019). This also provides a potential target for the treatment of certain ectopic mineralization diseases.

The present review focuses on the importance of applications of proteoglycans for biomineralization purposes in clinical practice. The application of exogenous GAGs and proteoglycans for rehabilitating bone defects in preclinical studies will also be addressed. Exogenous proteoglycans can be isolated from tissues and cell cultures or produced recombinantly. Because of their strong growth factor binding capacity, cell signal transduction potential and capability to guide osteogenic differentiation of progenitor cells (Dinoro et al., 2019), proteoglycans adopt a propitious role in bone tissue engineering, which will be duly deliberated.

Section snippets

Proteoglycans regulate biomineralization via their structural characteristics

Proteoglycans are heterogeneous macromolecules. They are divided into extracellular, pericellular, cell-surface-related and intracellular types according to their locations, homology at the protein and genomic levels and the presence of unique protein modules (Fig. 1). The GAG components of proteoglycans are linear polymers of repeating disaccharide units that are modified by sulfate groups at various positions (Table 1). Such an arrangement bestows the proteoglycans with a folded helical

Proteoglycans control physiological bone mineralization in a multifunctional manner

Bone is a unique mineralized tissue in which as much as 90 % of its organic matter is collagen (mainly type I). Among the non-collagenous proteins, proteoglycans account for 10–15 % of the wet weight of the ECM (Kram et al., 2020).

Implications of proteoglycans in pathological mineralization

Physiological mineralization is limited to bones, teeth and the hypertrophic zone of growth plate cartilage. Conversely, pathological mineralization may be found in any tissue (Schinke et al., 1999). These diseases include renal failure and atherosclerosis (often observed with vascular calcification), osteoarthritis (mineral deposits in the joints) and several genetic diseases in which the inactivation of specific genes leads to locally restricted pathological mineralization (Düsing et al., 2021

Exogenous GAGs and proteoglycans-based biomaterials for bone tissue regeneration

Scaffolds based on exogenous proteoglycans and GAGs have broad applications in bone tissue engineering (Rnjak-Kovacina et al., 2018). Their biomimetic properties include important cell binding motifs, natural-like biophysical characteristics, strong growth factor binding and cell signaling capabilities (Dinoro et al., 2019). To capture these biological functions, a series of biomaterials have been designed to combine with ready-made GAGs for bone tissue engineering. Because hyaluronan is not

Conclusions and perspectives

Proteoglycans have high structural complexity and heterogeneity. They participate in biomineralization through different mechanisms directly or indirectly. In bone, proteoglycans bind to a variety of cell surface receptors, cytokines, growth factors and directly interferes with plasma membrane receptors and surrounding matrix molecules to participate in cell-matrix interactions. They regulate the proliferation, differentiation, apoptosis and migration of osteoblast-related cells. Proteoglycans

CRediT authorship contribution statement

Jia-xin Hao: Conceptualization, Writing – original draft. Min-juan Shen: Writing – review & editing, Validation. Chen-yu Wang: Writing – review & editing. Jian-hua Wei: Visualization, Resources. Qian-qian Wan: Visualization. Yi-fei Zhu: Writing – review & editing. Tao Ye: Visualization, Resources. Meng-lin Luo: Visualization, Resources. Wen-pin Qin: Visualization. Yu-tao Li: Writing – review & editing. Kai Jiao: Funding acquisition, Conceptualization. Bin Zhao: Visualization, Resources. Li-na

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by innovative research team of high-level local universities in shanghai, Oral and maxillofacial regeneration and functional restoration, grants 81870805 and 82100971 from National Natural Science Foundation of China, grant 2020TD-033 from the Shaanxi Key Scientific and Technological Innovation Team and by the Youth Innovation Team of Shaanxi Universities.

References (138)

  • Y. Geng et al.

    SLRP interaction can protect collagen fibrils from cleavage by collagenases

    Matrix Biology : Journal of the International Society for Matrix Biology

    (2006)
  • R.C.H. Gresham et al.

    Growth factor delivery using extracellular matrix-mimicking substrates for musculoskeletal tissue engineering and repair

    Bioactive Materials

    (2021)
  • D. Hachim et al.

    Glycosaminoglycan-based biomaterials for growth factor and cytokine delivery: Making the right choices

    Journal of Controlled Release

    (2019)
  • I.A. Harten et al.

    The synthesis and secretion of versican isoform V3 by mammalian cells: A role for N-linked glycosylation

    Matrix Biology

    (2020)
  • H. He et al.

    Promotion effect of immobilized chondroitin sulfate on intrafibrillar mineralization of collagen

    Carbohydrate Polymers

    (2020)
  • G.K. Hunter et al.

    Effects of proteoglycan on hydroxyapatite formation under non-steady-state and pseudo-steady-state conditions

    Matrix

    (1992)
  • R.V. Iozzo et al.

    Proteoglycan form and function: A comprehensive nomenclature of proteoglycans

    Matrix Biology

    (2015)
  • L.M. Jenkins et al.

    Dually modified transmembrane proteoglycans in development and disease

    Cytokine & Growth Factor Reviews

    (2018)
  • O. Jeon et al.

    Affinity-based growth factor delivery using biodegradable, photocrosslinked heparin-alginate hydrogels

    Journal of Controlled Release

    (2011)
  • S. Kalamajski et al.

    Homologous sequence in lumican and fibromodulin leucine-rich repeat 5–7 competes for collagen binding

    Journal of Biological Chemistry

    (2009)
  • S. Kalamajski et al.

    The role of small leucine-rich proteoglycans in collagen fibrillogenesis

    Matrix Biology

    (2010)
  • S.E. Kim et al.

    Fabrication of a BMP-2-immobilized porous microsphere modified by heparin for bone tissue engineering

    Colloids and Surfaces B: Biointerfaces

    (2015)
  • C.B. Knudson et al.

    Cartilage proteoglycans

    Seminars in Cell and Developmental Biology

    (2001)
  • S. Liao et al.

    Potential and recent advances of microcarriers in repairing cartilage defects

    Journal of Orthopaedic Translation

    (2021)
  • C. Licini et al.

    Collagen and non-collagenous proteins molecular crosstalk in the pathophysiology of osteoporosis

    Cytokine & Growth Factor Reviews

    (2019)
  • M.S. Lord et al.

    The role of vascular-derived perlecan in modulating cell adhesion, proliferation and growth factor signaling

    Matrix Biology

    (2014)
  • P.J. Marie

    Fibroblast growth factor signaling controlling bone formation: An update

    Gene

    (2012)
  • I. Matsuo et al.

    Extracellular modulation of fibroblast growth factor signaling through heparan sulfate proteoglycans in mammalian development

    Current Opinion in Genetics & Development

    (2013)
  • N.D. Maulding et al.

    Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization

    Bone

    (2021)
  • Y. Mochida et al.

    Decorin modulates collagen matrix assembly and mineralization

    Matrix Biology

    (2009)
  • D. Nikitovic et al.

    The biology of small leucine-rich proteoglycans in bone pathophysiology

    Journal of Biological Chemistry

    (2012)
  • J. Pegge et al.

    Heparan sulfate proteoglycans regulate BMP signalling during neural crest induction

    Developmental Biology

    (2020)
  • P. Ramamurthy et al.

    Recombinant decorin glycoforms

    Journal of Biological Chemistry

    (1996)
  • G. Abatangelo et al.

    Hyaluronic acid: Redefining its role

    Cells

    (2020)
  • S. Bailey et al.

    Osteocalcin and osteopontin influence bone morphology and mechanical properties

    Annals of the New York Academy of Sciences

    (2017)
  • P. Behrens et al.

    Handbook of biomineralization edited by Peter Behrens and Edmund Ba

  • A.A. Belov et al.

    Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology

    Cold Spring Harbor Perspectives in Biology

    (2013)
  • A.D. Berendsen et al.

    Modulation of canonical Wnt signaling by the extracellular matrix component biglycan Source

    Proceedings of the National Academy of Sciences of the United States of America

    (2015)
  • P. Bianco et al.

    Expression and localization of the two small proteoglycans biglycan and decorin in developing human skeletal and non-skeletal tissues

    Journal of Histochemistry & Cytochemistry

    (1990)
  • J.P. Bilezikian et al.

    Principles of bone biology

  • P.C. Billings et al.

    Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: Mechanisms and mysteries

    Connective Tissue Research

    (2015)
  • A.L. Boskey et al.

    Effects of bone CS-proteoglycans, DS-decorin, and DS-biglycan on hydroxyapatite formation in a gelatin gel

    Calcified Tissue International

    (1997)
  • W.L. Chan et al.

    Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

    PLoS Genetics

    (2018)
  • C.C. Chen et al.

    The effects of proteoglycans from different cartilage types onin vitro hydroxyapatite proliferation

    Calcified Tissue International

    (1986)
  • C.-C. Chen et al.

    Mechanisms of proteoglycan inhibition of hydroxyapatite growth

    Calcified Tissue International

    (1985)
  • C.-C. Chen et al.

    The inhibitory effect of cartilage proteoglycans on hydroxyapatite growth

    Calcified Tissue International

    (1984)
  • S. Chen et al.

    The regulatory roles of small leucine-rich proteoglycans in extracellular assembly

    The FEBS Journal

    (2013)
  • A.C. Daquinag et al.

    Glycosaminoglycan modification of decorin depends on MMP14 activity and regulates collagen assembly

    Cells

    (2020)
  • A. De Maré et al.

    The role of sclerostin in bone and ectopic calcification

    International Journal of Molecular Sciences

    (2020)
  • A.A. DeCarlo et al.

    Perlecan domain 1 recombinant proteoglycan augments BMP-2 activity and osteogenesis

    BMC Biotechnology

    (2012)
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