ReviewRegulation of biomineralization by proteoglycans: From mechanisms to application
Graphical abstract
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)
- et al.
Affinity hydrogels for protein delivery
Trends in Pharmacological Sciences
(2021) - et al.
Dual roles of heparanase in human carotid plaque calcification
Atherosclerosis
(2019) - et al.
Bone marrow-derived heparan sulfate potentiates the osteogenic activity of bone morphogenetic protein-2 (BMP-2)
Bone
(2012) - et al.
Sulfated polysaccharide-based scaffolds for orthopaedic tissue engineering
Biomaterials
(2019) - et al.
Role of EGF receptor signaling on morphogenesis of eyelid and meibomian glands
Experimental Eye Research
(2017) - et al.
GORAB missense mutations disrupt RAB6 and ARF5 binding and golgi targeting
Journal of Investigative Dermatology
(2015) - et al.
Bioinspired double polysaccharides-based nanohybrid scaffold for bone tissue engineering
Colloids and Surfaces B: Biointerfaces
(2016) - et al.
Effects of alginate/chondroitin sulfate-based hydrogels on bone defects healing
Materials Science and Engineering: C
(2020) - et al.
Hyaluronan biology: A complex balancing act of structure, function, location and context
Matrix Biology
(2019) - et al.
SLRP interaction can protect collagen fibrils from cleavage by collagenases
Matrix Biology
(2006)
SLRP interaction can protect collagen fibrils from cleavage by collagenases
Matrix Biology : Journal of the International Society for Matrix Biology
Growth factor delivery using extracellular matrix-mimicking substrates for musculoskeletal tissue engineering and repair
Bioactive Materials
Glycosaminoglycan-based biomaterials for growth factor and cytokine delivery: Making the right choices
Journal of Controlled Release
The synthesis and secretion of versican isoform V3 by mammalian cells: A role for N-linked glycosylation
Matrix Biology
Promotion effect of immobilized chondroitin sulfate on intrafibrillar mineralization of collagen
Carbohydrate Polymers
Effects of proteoglycan on hydroxyapatite formation under non-steady-state and pseudo-steady-state conditions
Matrix
Proteoglycan form and function: A comprehensive nomenclature of proteoglycans
Matrix Biology
Dually modified transmembrane proteoglycans in development and disease
Cytokine & Growth Factor Reviews
Affinity-based growth factor delivery using biodegradable, photocrosslinked heparin-alginate hydrogels
Journal of Controlled Release
Homologous sequence in lumican and fibromodulin leucine-rich repeat 5–7 competes for collagen binding
Journal of Biological Chemistry
The role of small leucine-rich proteoglycans in collagen fibrillogenesis
Matrix Biology
Fabrication of a BMP-2-immobilized porous microsphere modified by heparin for bone tissue engineering
Colloids and Surfaces B: Biointerfaces
Cartilage proteoglycans
Seminars in Cell and Developmental Biology
Potential and recent advances of microcarriers in repairing cartilage defects
Journal of Orthopaedic Translation
Collagen and non-collagenous proteins molecular crosstalk in the pathophysiology of osteoporosis
Cytokine & Growth Factor Reviews
The role of vascular-derived perlecan in modulating cell adhesion, proliferation and growth factor signaling
Matrix Biology
Fibroblast growth factor signaling controlling bone formation: An update
Gene
Extracellular modulation of fibroblast growth factor signaling through heparan sulfate proteoglycans in mammalian development
Current Opinion in Genetics & Development
Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization
Bone
Decorin modulates collagen matrix assembly and mineralization
Matrix Biology
The biology of small leucine-rich proteoglycans in bone pathophysiology
Journal of Biological Chemistry
Heparan sulfate proteoglycans regulate BMP signalling during neural crest induction
Developmental Biology
Recombinant decorin glycoforms
Journal of Biological Chemistry
Hyaluronic acid: Redefining its role
Cells
Osteocalcin and osteopontin influence bone morphology and mechanical properties
Annals of the New York Academy of Sciences
Handbook of biomineralization edited by Peter Behrens and Edmund Ba
Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology
Cold Spring Harbor Perspectives in Biology
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
Expression and localization of the two small proteoglycans biglycan and decorin in developing human skeletal and non-skeletal tissues
Journal of Histochemistry & Cytochemistry
Principles of bone biology
Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: Mechanisms and mysteries
Connective Tissue Research
Effects of bone CS-proteoglycans, DS-decorin, and DS-biglycan on hydroxyapatite formation in a gelatin gel
Calcified Tissue International
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
The effects of proteoglycans from different cartilage types onin vitro hydroxyapatite proliferation
Calcified Tissue International
Mechanisms of proteoglycan inhibition of hydroxyapatite growth
Calcified Tissue International
The inhibitory effect of cartilage proteoglycans on hydroxyapatite growth
Calcified Tissue International
The regulatory roles of small leucine-rich proteoglycans in extracellular assembly
The FEBS Journal
Glycosaminoglycan modification of decorin depends on MMP14 activity and regulates collagen assembly
Cells
The role of sclerostin in bone and ectopic calcification
International Journal of Molecular Sciences
Perlecan domain 1 recombinant proteoglycan augments BMP-2 activity and osteogenesis
BMC Biotechnology
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