A Novel Approach: Proteoglycan Mimics in Bone Tissue Engineering

The Role of Proteoglycans in Bone Structure and Function

When we think of bones, we often imagine them as rigid structures that support our bodies, protect vital organs, and enable movement. While bones are indeed strong and sturdy, they are also dynamic and complex tissues composed of a variety of cells and molecules that work together to maintain their strength and flexibility. To understand bone structure and function, it’s essential to review the key components of bone tissue:  the mineralized matrix and the organic matrix. The mineralized matrix is primarily made of hydroxyapatite crystals, a calcium phosphate compound that provides bones with their hardness and strength. The organic matrix, on the other hand, is composed mainly of collagen fibers and proteoglycans. While collagen fibers give bone its tensile strength and resistance to stretching, proteoglycans contribute to the flexibility and resilience of bone.

Figure: Distinct roles of Proteoglycans

Source: (Hao et al., 2022)

What are Proteoglycans?

Proteoglycans are large, complex molecules consisting of a core protein attached to one or more glycosaminoglycan (GAG) chains. GAGs are long, unbranched polysaccharides that are highly negatively charged due to the presence of sulfate and carboxyl groups. This negative charge allows them to attract water and ions, contributing to structural and functional properties of many tissues, including cartilage, skin, and, importantly, bone.  Common GAGs found in proteoglycans include heparan sulfate, chondroitin sulfate, hyaluronic acid, keratan sulfate, and dermatan sulfate. The specific composition and structure of the GAG chains determine the unique functions of different proteoglycans in various tissues.

Proteoglycans in Bone

In bone tissue, proteoglycans play both structural and functional roles. They are key regulators of bone development and homeostasis, influencing communication between cells and the extracellular matrix.  Due to their high negative charge, proteoglycans generate attractive forces and nucleation sites for cations such as calcium and phosphate ions, facilitating biomineralization. Additionally, the negatively charged sulfate ions on GAGs like heparan sulfate help sequester and stabilize growth factors containing positively charged amino acids through electrostatic forces. This interaction is crucial for modulating signaling pathways involved in bone growth and repair.

Small Leucine-Rich Proteoglycans in Bone Homeostasis

One important class of proteoglycans in bone is the small leucine-rich proteoglycans (SLRPs). SLRPs are crucial for maintaining bone homeostasis and participate in all phases of bone formation including cell proliferation, mineralization, osteogenesis, and bone remodeling. SLRPs also regulate collagen fibrillogenesis, which is the organization and production of collagen fibers. Here are some key SLRPs in bone:

1. Decorin: Decorin binds to collagen fibers, regulating their organization and assembly. This interaction is essential for maintaining the integrity and strength of the bone matrix. Decorin also modulates the activity of growth factors, such as transforming growth factor-beta (TGF-β), which is involved in bone remodeling and repair.

2. Biglycan: Similar to decorin, biglycan interacts with collagen fibers and influences the mineralization process by regulating the deposition of hydroxyapatite crystals in the bone matrix. It is expressed during cell proliferation and mineralization and has a role in regulating the activity of bone cells, including osteoblasts (bone-forming cells) and osteoclasts (bone resorbing cells).

3. Osteoadherin (Osteomodulin): Osteoadherin is expressed in mineralized tissues, including bones and teeth. It binds to hydroxyapatite crystals, contributing to the mineralization of bone. By interacting with collagen fibers, osteoadherin helps to organize the bone matrix and maintain its structural integrity.

4. Asporin: This unique member of the SLRP family contains a distinctive series of aspartate residues in the N-terminal region, with some polymorphisms linked to osteoarthritis and intervertebral disc disease. In skeletal tissue, asporin promotes collagen mineralization and acts as a negative regulator of chondrogenesis.

5. Keratocan: This keratan sulfate proteoglycan plays a role in regulating cell proliferation and modulation of osteoblast differentiation.

6. Versican: Although not an SLRP, Versican is a large proteoglycan in bone that plays a significant role in bone. It is known for its ability to bind water and contribute to the viscoelastic properties of the extracellular matrix. In bone, versican helps modulate the mechanical properties of the tissue, providing resistance to compressive forces.

A Hyper-Crosslinked Carbohydrate Polymer as a Proteoglycan Mimic

Advances in bone tissue engineering have led to the development of biomimetic materials that replicate the function of natural proteoglycans. One such material is a hyper-crosslinked carbohydrate-based polymer (Osteo-P® BGS). This novel polymer displays similar characteristics to those of proteoglycans, being biocompatible, osteoconductive, and promoting significant bone regeneration in vivo.

Osteo-P® BGS scaffolds mimic essential properties of proteoglycans, including strong binding with growth factors and high density, interconnected pores with a large surface area, which facilitate absorption, nutrient transfer, and cell adhesion. Remarkably, these scaffolds have demonstrated exceptional adherence of hematopoietic (CD34+) and mesenchymal stem cells, promoting enhanced osteogenic (bone-forming) and angiogenic (blood vessel-forming) properties.

Conclusion

Understanding the structure and function of proteoglycans in bone biology not only provides insights into how our skeletal system functions, but also opens potential avenues for developing new treatments for bone-related diseases and conditions. As research progresses, materials that mimic the properties of proteoglycans, like Osteo-P® BGS, offer promising strategies for bone regeneration and repair.

For more in-depth reading, refer to “Osteogenic Cells and Microenvironment of Early Bone Development and Clinical Implication” (D. Kim & C. Lee, 2023) and “Hyper-Crosslinked Carbohydrate Polymer for Repair of Critical-Sized Bone Defects” (Koleva et al., 2019).

References:

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D. Kim, K., & C. Lee, C. (2023). Osteogenic Cells and Microenvironment of Early Bone Development and Clinical Implication. In J. Jin Wang, G. Wang, X. Lv, Z. Sun, & K. Sunil Mahapure (Eds.), Frontiers in Spinal Neurosurgery. IntechOpen. https://doi.org/10.5772/intechopen.1002037

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