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A high-risk osteoarthritis mutation in COL6A3 alters the mechanobiologic response of chondrocytes derived from human induced pluripotent stem cells

ABSTRACT: Osteoarthritis (OA) is a complex disease arising from a combination of genetic, biological, and mechanical risk factors that act, in part, to alter chondrocyte homeostasis. Our recent exome sequencing studies identified a causal OA variant in COL6A3, a monomeric unit of collagen type VI that serves as a distinguishing component of the pericellular matrix (PCM), a key transducer of mechanical and biochemical signals for the chondrocyte. To study the effect of this mutation, human induced pluripotent stem cell (hiPSC)-derived chondrocytes, genetically edited to harbor the COL6A3 mutation, were used as an in vitro model to investigate chondrocyte mechanobiology and pathobiology. COL6A3 mutant chondrocytes exhibited reduced expression of key matrix proteins, suggesting altered PCM structure and composition. Functional analyses revealed altered mechanotransduction, characterized by heightened osmotically induced calcium signaling and reduced anabolic response to TRPV4 activation, at the transcriptional level and in matrix biosynthesis. RNA sequencing identified dysregulated pathways and aberrant TRPV4 signaling in mutant chondrocytes following mechanical loading. The presence of the COL6A3 mutation resulted in disrupted circadian rhythms, with increased BMAL1 expression and a significant phase shift, suggesting a link between the PCM and the circadian clock. Finally, COL6A3 mutant chondrocytes exhibited exacerbated catabolic response to interleukin-1, a key inflammatory cytokine in OA. Our study demonstrates the utility of a human iPSC-based system for studying the pathophysiology of specific OA risk alleles. These findings highlight the impact of the COL6A3 variant on chondrocyte physiology and support targeting mechanotransduction signaling pathways as a potential strategy for OA intervention in this case.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293777 | GEO | 2025/04/08

REPOSITORIES: GEO

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Project description:Autologous chondrocyte transplantation (ACT) is a routine technique to regenerate focal cartilage lesions. However, patients with osteoarthritis (OA) are lacking an appropriate long-lasting treatment alternative, partly since it is not known if chondrocytes from OA patients have the same chondrogenic differentiation potential as chondrocytes from donors not affected by OA. Articular chondrocytes from patients with OA undergoing total knee replacement (Mankin Score >3, AhlbÃ¤ck Score >2) and from patients undergoing ACT, here referred to as normal donors (ND), were isolated applying protocols used for ACT. Their chondrogenic differentiation potential was evaluated both in high-density pellet and scaffold (Hyaff-11) cultures by histological proteoglycan assessment (Bern Score) and immunohistochemistry for collagen types I and II. Chondrocytes cultured in monolayer and scaffolds were subjected to gene expression profiling using genome-wide oligonucleotide microarrays. Expression data were verified by using quantitative RT-PCR. Chondrocytes from ND and OA donors demonstrated accumulation of comparable amounts of cartilage matrix components, including sulphated proteoglycans and collagen types I and II. The mRNA expression of cartilage markers (COL2A1, COMP, aggrecan, CRTL1, SOX9) and genes involved in matrix synthesis (biglycan, COL9A2, COL11A1, TIMP4, CILP2) was highly induced in 3D cultures of chondrocytes from both donor groups. Genes associated with hypertrophic or OA cartilage (COL10A1, RUNX2, periostin, ALP, PTHR1, MMP13, COL1A1, COL3A1) were not significantly regulated between the two groups of donors. The expression of 661 genes, including COMP, FN1, and SOX9, were differentially regulated between OA and ND chondrocytes cultured in monolayer. During scaffold culture, the differences diminished between the OA and ND chondrocytes, and only 184 genes were differentially regulated. Only few genes were differentially expressed between OA and ND chondrocytes in Hyaff-11 culture. The risk of differentiation into hypertrophic cartilage does not seem to be increased for OA chondrocytes. Our findings suggest that the chondrogenic capacity is not significantly affected by OA and OA chondrocytes fulfill the requirements for matrix-associated ACT. Experiment Overall Design: Gene expression profiles of monolayer cultures (ML; passage 2) and Hyaff-11 scaffold cultures (3D; 14 days in vitro) of chondrocytes from 3 normal donors (ND; underwent ACT treatment) and 3 donors suffering from Osteoarthritis (OA; underwent knee replacement surgery) were determined. Comparative analyses between 3D and ML cultures (3D vs. ML) were performed to assess differentiation capacity of ND and OA chondrocytes. Furthermore, OA-related differences were determined comparing OA and ND monolayers as well as scaffold cultures (each OA vs. ND).

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A high-risk osteoarthritis mutation in COL6A3 alters the mechanobiologic response of chondrocytes derived from human induced pluripotent stem cells

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