Reduced thrombospondin-1 is associated with altered collagen-rich matrix organization in discoid lateral meniscus
TL;DR
In donor-derived models, THBS1 knockdown in NLM cells reduced area-confluence trajectories, increased migration, and decreased collagen-rich matrix in 4-week spheroids, whereas THBS1 overexpression in DLM cells produced reciprocal changes; aggrecan was not consistently altered.
Abstract
Discoid lateral meniscus (DLM) is susceptible to tearing and degeneration, but the molecular basis of its altered extracellular matrix (ECM) remains unclear. We integrated histology, electron microscopy, transcriptomics, quantitative proteomics, and donor-derived cell and spheroid models to investigate the association between thrombospondin-1 (THBS1) and matrix organization in symptomatic DLM. Compared with traumatic morphologically normal lateral meniscus (NLM), DLM tissue contained fewer cells per analyzed image (mean difference, −16.10; 95% confidence interval (CI), −23.49 to −8.71; P < 0.0001); lower type-I and II collagen signals; and thinner, less dense, and less organized collagen fibrils. Cross-omics analysis nominated THBS1 and ECM-receptor interaction, and independent assays confirmed a 6.67-fold lower THBS1 protein abundance in DLM (95% CI, 5.04 to 8.27; P < 0.0001). In donor-derived models, THBS1 knockdown in NLM cells reduced area-confluence trajectories, increased migration, and decreased collagen-rich matrix in 4-week spheroids, whereas THBS1 overexpression in DLM cells produced reciprocal changes; aggrecan was not consistently altered. These data associate reduced THBS1 with altered collagen-rich matrix organization and support a functional contribution in vitro . The cross-sectional clinical comparison does not establish chronology, and the spheroid experiments do not demonstrate a fibrillogenesis-specific mechanism.
