Key Takeaways & Executive Findings
- •• Type VI collagen maintains bone homeostasis by promoting osteoblast matrix bridge formation and inhibiting TNF-α/NF-κB p65-mediated osteoclast activation. • Dysregulation of type VI collagen is linked to osteoporosis (α2 chain epigenetic suppression), osteoarthritis (pericellular matrix degradation), and bone tumors (α1 chain overexpression). • Type VI collagen enhances osteogenic properties of scaffolds and its degradation products serve as diagnostic biomarkers for fibrotic diseases. • Antisense oligonucleotide therapy shows promise for correcting splice-site mutations in type VI collagen-related disorders.
Abstract
BACKGROUND: As a key structural protein in the extracellular matrix, type VI collagen plays a critical role in skeletal development, homeostasis, and repair through its unique tetrameric microfibrillar network. Recent studies have found that abnormal expression of type VI collagen is closely related to skeletal diseases such as osteoporosis, osteoarthritis, and bone tumors, but its multidimensional regulatory mechanisms and translational application potential still need systematic summary. OBJECTIVE: To review the structural characteristics and biological functions of type VI collagen in the skeletal system, clarify the mechanism of type VI collagen in skeletal diseases, and explore the translational application prospects of type VI collagen in biomarker development, tissue engineering material construction, and therapeutic target design. METHODS: A systematic search of PubMed, Web of Science, Elsevier, and CNKI databases from January 1982 to May 2025 was conducted, including research articles and reviews, excluding duplicates and low-quality literature. Finally, 69 articles (68 in English and 1 in Chinese) were included for systematic content integration and analysis. RESULTS AND CONCLUSION: Type VI collagen affects bone health through a triple regulatory network: (1) Bone formation and resorption balance: promotes osteoblast 'matrix bridge' connection and inhibits tumor necrosis factor α/nuclear factor κB p65 subunit signaling pathway-mediated osteoclast activation; (2) Disease mechanisms: in osteoporosis, the α2 chain of type VI collagen is epigenetically inhibited by miR-128-2-5p; in early osteoarthritis, pericellular matrix degradation occurs; in bone tumors, the α1 chain of type VI collagen is highly expressed; (3) Translational applications: type VI collagen can enhance the osteogenic efficacy of scaffold materials; specific serum degradation products of type VI collagen can serve as diagnostic markers for fibrotic diseases; antisense oligonucleotide technology has been successfully used to correct abnormal splicing caused by splice site mutations. Type VI collagen is a core regulatory hub for maintaining bone homeostasis, integrating the structural support and signal transduction functions of the extracellular matrix to regulate the dynamic balance of bone formation and resorption. Degradation products and tissue distribution patterns of type VI collagen can provide new diagnostic markers for skeletal diseases, and gene-targeted therapy and type VI collagen-enhanced biological scaffolds are expected to become innovative treatment strategies for osteoporosis and bone defects. Future research needs to break through the technical bottleneck of tissue-targeted delivery and deepen the dynamic expression atlas research based on multi-omics.
1. Introduction
The skeletal system not only serves as the body's support structure but is also a highly dynamic metabolic organ whose health depends on the precise balance between bone formation and resorption, known as 'bone homeostasis' [1]. The collagen family is the main organic component of the bone extracellular matrix, with type I collagen being the primary load-bearing fiber. However, recent studies have found that non-fibrous collagens, such as type VI collagen, play an indispensable role in regulating bone cell function and tissue homeostasis [1-2].
Type VI collagen is an important component of the extracellular matrix, widely distributed in various tissues, especially enriched in the skeletal system. It not only plays a fundamental role in maintaining tissue structural integrity but also actively participates in key biological processes such as cell signaling, adhesion, proliferation, and differentiation. Type VI collagen has diverse functions and exerts irreplaceable regulatory value in skeletal development, tissue repair, and disease progression. Studies have shown that loss or dysfunction of type VI collagen expression is closely related to the occurrence and development of skeletal diseases such as osteoporosis and arthritis [3]. Furthermore, type VI collagen is also involved in early skeletal development and mineralization regulation.
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Dong Shiming, Xie Zhenzi, Tao Rongrong, Mardan·Mamat, Ma Hairong (2026). Type VI collagen: a multifunctional regulator in bone homeostasis and tissue engineering. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21589
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Frequently Asked Questions
What is type VI collagen and why is it important for bone health?
Type VI collagen is a key extracellular matrix protein that forms unique beaded microfibrils. It is crucial for maintaining bone homeostasis by supporting tissue structure, promoting osteoblast function, and regulating osteoclast activity.
How does type VI collagen contribute to osteoporosis?
In osteoporosis, the α2 chain of type VI collagen is epigenetically suppressed by miR-128-2-5p, leading to reduced collagen expression and impaired bone formation, contributing to bone loss.
What role does type VI collagen play in osteoarthritis?
In early osteoarthritis, the pericellular matrix containing type VI collagen undergoes degradation, which may compromise the mechanical integrity of cartilage and contribute to disease progression.
Can type VI collagen be used in tissue engineering?
Yes, type VI collagen can be integrated into bone tissue engineering scaffolds to enhance their osteogenic properties, promoting better bone regeneration.
Are there any therapeutic strategies targeting type VI collagen?
Antisense oligonucleotide technology has been used to correct splice-site mutations in type VI collagen, and gene-targeted therapies are being explored for treating skeletal diseases.
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