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Dissertation
The regulatory roles of decorin in the maintenance and remodeling of articular cartilage matrix during aging
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2025
DOI:
https://doi.org/10.17918/00011164
Abstract
Osteoarthritis (OA) is the most prevalent musculoskeletal disease worldwide, with aging recognized as its leading risk factor. Age-related degeneration of articular cartilage involves not only cellular changes, but also progressive deterioration of the extracellular matrix (ECM), a composite of collagen II fibrils and proteoglycans that ensure proper joint load-bearing, lubrication, and energy dissipation functions. Decorin, a small leucine-rich proteoglycan, interacts directly with collagen II and aggrecan, influencing fibrillogenesis, aggrecan retention, and the structural integrity of cartilage matrix. Although decorin's structural and biological roles are well studied in other tissues, its function in maintaining articular cartilage during aging has remained unclear. This work integrated AFM-based biomechanical testing, collagen fibril structural characterization, chondrocyte transcriptional changes, chondrocyte mechanobiology, in-vitro molecular assays and ex-vivo explant study to elucidate age-related alterations in murine cartilage ECM and to define decorin's role in cartilage maintenance. In wild-type mice aged 3, 12, and 22 months, natural aging was associated with reduced sulfated glycosaminoglycan (sGAG) content, thickened surface collagen fibrils, and significantly decreased cartilage effective modulus, without pronounced early loss of chondrocyte calcium signaling. These findings contrasted with rapid matrix and mechanotransduction decline observed in post-traumatic OA, indicating distinct aging versus injury-driven degeneration pathways. Using a cartilage-specific inducible decorin knockout DcncKO model (Dcnf/f/AcanCreER) induced after skeletal maturity, the study demonstrated that loss of decorin accelerates age-related ECM degradation, fibrillation and remodeling. By 9 months, DcncKO femoral cartilage developed a sGAG-absent, highly aligned collagen surface layer, despite preserved chondrocyte phenotype. By 18 months, severe OA-like pathology emerged, including surface erosion, fibrotic collagen I-rich "scar" layer deposition by infiltrating matrix-producing cells, and marked structural disorganization. Single-cell RNA sequencing revealed minimal transcriptional changes at 9 months of age, but identified a distinct, fibrogenic cell population by 18 months, contributing to the observed pathological remodeling at this age. Notably, cartilage surface remodeling emerged before detectable transcriptional changes in chondrocytes, including those in TGF-[beta] signaling, highlighting decorin's structural role as a collagen/aggrecan stabilizer that precedes and likely triggers downstream biological responses. In vitro biophysical assays confirmed that decorin directly binds to collagen II fibrils, reducing their diameter, limiting shear-induced fibril alignment with and without cellular element, and strengthening the superficial fibrillar network in explants. Loss of decorin in tibial cartilage also impaired pericellular and territorial ECM mechanical properties, diminished chondrocyte calcium responses, and disrupted TRPV4-mediated mechanosensing, indicating matrix structural changes related mechanobiological deficits. In summary, this thesis establishes decorin as a critical structural regulator of cartilage ECM during aging, maintaining surface fibril architecture, stabilizing aggrecan content, and preserving mechanotransduction microenvironments. Its absence accelerates matrix deterioration, promotes fibrotic remodeling, and precipitates OA onset. These findings position decorin as a promising therapeutic target for prolonging cartilage function and delaying age-related and degenerative joint disease progression.
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Details
- Title
- The regulatory roles of decorin in the maintenance and remodeling of articular cartilage matrix during aging
- Creators
- Mingyue Fan
- Contributors
- Lin Han (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 127 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991022093055704721