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Proteoglycans in Embryonic Bone Development: The Unsung Heroes

Molecular Matrix, Inc. has developed Osteo-P® BGS, a hyper-crosslinked polysaccharide bone graft substitute that mimics proteoglycans and is osteoconductive for bone repair. Osteo-P® BGS is designed to model the intricate processes of embryonic bone development. To learn more about embryonic bone and proteoglycans see below or visit


Embryonic bone development is a remarkably intricate and finely tuned process, orchestrated by a myriad of cellular, molecular, and matrix interactions. The process involves a symphony of cell types, extracellular matrices, and biological signals that work in concert to create a skeletal system that provides structural support and stability, mineral storage, and protection of vital organs. The skeletal system is somewhat unique among organ systems for its lifelong ability for bone deposition, absorption, and remodeling, providing a natural regenerative capacity unless the bone defect is too large (critical-sized) or a therapeutic fusion is required as in spinal fusion. It seems appropriate to review the embryonic score for bone development when composing better repair strategies for filling bony gaps or defects, or when fusions are required. While much attention is given to osteogenic cells such as osteoblasts and osteoclasts, and osteogenic signals such as BMP-2, the core extracellular matrix molecules such as proteoglycans play a crucial, yet often overlooked, role in the developmental orchestra.  (Kim and Lee, 2023)


What are Proteoglycans?


Proteoglycans are large molecules composed of a core protein (‘proteo’) attached to one or more ‘glycan’ glycosaminoglycan (GAG) chains. Interestingly, there are only about 50 proteoglycan protein cores, many of which are highly conserved across species. The GAG chains, on the other hand, are long, unbranched polysaccharides that are highly negatively charged due to the presence of sulfate and carboxyl groups. GAGs vary widely in number, degree of sulfation, carboxylation, and quality, thus creating a rich proteoglycan diversity that contributes to a wide range of biological activities and influences cell behavior and physiology. (Rnjak-Kovacina, et al., 2018)

Proteoglycans in Different Stages of Bone Development

1. Mesenchymal Condensation:

During the initial stages of bone development, mesenchymal cells aggregate and form condensations. Proteoglycans, particularly those in the pericellular matrix, facilitate cell-cell and cell-matrix interactions essential for this process.

2. Chondrogenesis and Cartilage Formation:

In the cartilage template stage of endochondral ossification, proteoglycans such as aggrecan provide the cartilage with unique properties, including high tensile strength and resistance to compression. These properties are crucial for the cartilage to serve as a scaffold for subsequent bone formation.

3. Ossification: 

During intramembranous and endochondral ossification, proteoglycans regulate the deposition of mineral content and the organization of collagen fibers. This ensures the proper formation of bone matrix and its eventual mineralization.


Functions of Proteoglycans in Bone Development

1. Regulation of Cell Activity including Proliferation, Differentiation, and Adhesion

Proteoglycans, such as aggrecan and versican, bind to growth factors like FGFs and BMPs which, in turn, modulate the availability and activity of these growth factors, ultimately affecting the proliferation and differentiation of MSC into osteoblasts. Proteoglycans also interact with cell surface receptors, such as integrins, to mediate cell adhesion, migration, and organization. This is essential for proper placement and alignment of cells during bone formation.

2. Extracellular Matrix Organization

Some proteoglycans, such as decorin and biglycan, regulate collagen fibrillogenesis and mineral deposition, thus affecting matrix mineralization. They bind to collagen fibers and influence nucleation of hydroxyapatite crystals, which are essential for bone mineralization. Biglycan knock-out mice have reduced bone mass and an osteoporosis-like phenotype with age-dependent osteopenia. (Xu et al., 1998) Reductions in osteoblast differentiation, cortical thickness and bone mechanics was shown in these knockouts. (Shanier et al., 2023) The long GAG chains of proteoglycans become hydrated under physiological conditions forming a hydrated gel that resists compressive forces and contributes to structural support. This is particularly important in cartilage, which is a template for endochondral ossification.

3. Signaling Pathway Modulation

Proteoglycans, especially the heparan-sulfate proteoglycans, are often found attached or near the cell membrane where they are thought to act as co-receptors or to play a role in stabilization of membrane-growth factor signaling complexes (Xie et al., 2023). The negatively-charged GAG chains of proteoglycans bind positively-charged amino acids of growth factors such as those in the Wnt, BMP, and TGF-B signaling pathways. They can enhance or inhibit these pathways, thereby fine-tuning the balance between bone formation and resorption.


Proteoglycans, though often overshadowed by other components of bone development, are indispensable players in this complex process. They regulate cellular activities, organize the extracellular matrix, and modulate key signaling pathways, ensuring the proper formation and mineralization of bones. Understanding the role of proteoglycans in embryonic bone development opens new avenues for therapeutic strategies in bone-related disorders and important keys to the composition of better bone graft substitutes.




Kim KD, Lee CC. “Osteogenic Cells and Microenvironment of Early Bone Development and Clinical Implication.” Frontiers in Spinal Neurosurgery, Ch. 7, edited by Wang, J.J., Wang G., Lv X., Sun Z., and Mahapure K.S., IntechOpen, 14 July 2023. DOI: 10.5772/intechopen.1002037


Rnjak-Kovacina J, Tang F, Whitelock JM, Lord MS. Glycosaminoglycan and Proteoglycan-Based Biomaterials: Current Trends and Future Perspectives. Adv Healthc Mater. 2018 Mar;7(6):e1701042. DOI: 10.1002/adhm.201701042. Epub 2017 Dec 6. PMID: 29210510.


Shainer R, Kram V, Kilts TM, Li L, Doyle AD, Shainer I, Martin D, Simon CG Jr, Zeng-Brouwers J, Schaefer L, Young MF. Genomics and Computational Biology Core. Biglycan regulates bone development and regeneration. Front Physiol. 2023 Feb 16;14:1119368. DOI: 10.3389/fphys.2023.1119368. PMID: 36875017; PMCID: PMC9979216.


Xie C, Schaefer L, Iozzo RV. Global impact of proteoglycan science on human diseases. iScience. 2023 Oct 4;26(11):108095. DOI: 10.1016/j.isci.2023.108095. PMID: 37867945; PMCID: PMC10589900.


Xu T, Bianco P, Fisher LW, Longenecker G, Smith E, Goldstein S, et al. (1998). Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice. Nat. Genet. 20, 78–82. DOI: 10.1038/1746




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