Shoulders

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SEEK ID: https://nextseek-dev.mit.edu/investigations/5

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Created: 21st Jan 2026 at 15:07

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Demo Demo

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Institutions: BMC-BioMicro Center (MIT)

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Failed cellular surveillance enables pathogenic matrix deposition in a COL2A1-related osteoarthritis

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Kathryn M. Yammine, Sophia Mirda Abularach, Michael Xiong, Seo-yeon Kim, Agata A. Bikovtseva, Vincent L. Butty, Richard P. Schiavoni, John F. Bateman, Shireen R. Lamandé, and Matthew D. Shoulders

A dbGaP Submission is underway and metadata will be updated at the completion of submission. The remaining of the data and metadata are available here.

DOI: 10.1101/2024.11.07.622468.

Abstract:

Objectives Mutations in the procollagen-II gene (COL2A1) ...

Submitter: Demo Demo

Investigation: Shoulders

Assays: Cell Imaging - Data Linked, Gene Expression Analysis - Data Linked, LC - MS/MS (Proteomics) - Data Linked, Library Creation - Metadata, Proteomics Analysis - Data Linked, RNA Extraction - Metadata, Short Read Sequencing - Data Linked, iPSC Culture and Chondronoid Formation - Metadata

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Created: 21st Jan 2026 at 15:08, Last updated: 25th Aug 2026 at 14:13

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iPSC Culture and Chondronoid Formation - Metadata

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Investigation: Shoulders

Study: Failed cellular surveillance enables pathogenic...

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SOPs: P.SHO-250605-V1_Collagen_Imaging.docx, P.SHO-250605-V1_Collagen_Proteomics.docx, P.SHO-250605-V1_Collagen_RNAseq.docx, P.SHO-250605-V1_Collagen_iPSC.docx

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Created: 21st Jan 2026 at 15:12, Last updated: 22nd Jan 2026 at 20:24

Cell Imaging - Data Linked

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Assay type: Experimental Assay Type

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Investigation: Shoulders

Study: Failed cellular surveillance enables pathogenic...

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SOPs: P.SHO-250605-V1_Collagen_Imaging.docx

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Created: 21st Jan 2026 at 15:12, Last updated: 22nd Jan 2026 at 15:59

RNA Extraction - Metadata

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Assay type: Experimental Assay Type

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Investigation: Shoulders

Study: Failed cellular surveillance enables pathogenic...

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SOPs: P.SHO-250605-V1_Collagen_RNAseq.docx

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Created: 21st Jan 2026 at 15:12, Last updated: 22nd Jan 2026 at 16:19

LC - MS/MS (Proteomics) - Data Linked

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Investigation: Shoulders

Study: Failed cellular surveillance enables pathogenic...

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SOPs: P.SHO-250605-V1_Collagen_Proteomics.docx

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Created: 21st Jan 2026 at 15:12, Last updated: 22nd Jan 2026 at 16:01

Library Creation - Metadata

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Investigation: Shoulders

Study: Failed cellular surveillance enables pathogenic...

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SOPs: P.SHO-250605-V1_Collagen_RNAseq.docx

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Created: 21st Jan 2026 at 15:12, Last updated: 22nd Jan 2026 at 16:19

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P.SHO-250605-V1_Collagen_iPSC.docx

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Investigations: Shoulders

Studies: Failed cellular surveillance enables pathogenic...

Assays: iPSC Culture and Chondronoid Formation - Metadata

Created: 22nd Jan 2026 at 20:24, Last updated: 22nd Jan 2026 at 20:24

P.SHO-250605-V1_Collagen_RNAseq.docx

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Investigations: Shoulders

Studies: Failed cellular surveillance enables pathogenic...

Assays: Gene Expression Analysis - Data Linked, Library Creation - Metadata, RNA Extraction - Metadata, Short Read Sequencing - Data Linked, iPSC Culture and Chondronoid Formation - Metadata

Created: 22nd Jan 2026 at 16:19, Last updated: 22nd Jan 2026 at 16:19

P.SHO-250605-V1_Collagen_Proteomics.docx

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Investigations: Shoulders

Studies: Failed cellular surveillance enables pathogenic...

Assays: LC - MS/MS (Proteomics) - Data Linked, Proteomics Analysis - Data Linked, iPSC Culture and Chondronoid Formation - Metadata

Created: 22nd Jan 2026 at 16:01, Last updated: 22nd Jan 2026 at 16:01

P.SHO-250605-V1_Collagen_Imaging.docx

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Submitter: Demo Demo

Investigations: Shoulders

Studies: Failed cellular surveillance enables pathogenic...

Assays: Cell Imaging - Data Linked, iPSC Culture and Chondronoid Formation - Metadata

Created: 22nd Jan 2026 at 15:59, Last updated: 22nd Jan 2026 at 15:59

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Failed cellular surveillance enables pathogenic matrix deposition in a COL2A1-related osteoarthritis.

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Abstract (Expand)

Mutations in the COL2A1 gene, encoding procollagen-II, cause various chondrodysplasias, including precocious osteoarthritis with mild spondyloepiphyseal dysplasia engendered by the p.Arg719Cys substitution. … The molecular mechanisms underlying these disorders remain incompletely understood, largely owing to the absence of models faithfully recapitulating the human disease. Here, we developed an in vitro human cartilage model using isogenic induced pluripotent stem cell (iPSC) lines carrying either wild-type or Arg719Cys COL2A1. Directed differentiation into chondrocytes yielded cartilage tissues that were analyzed by immunohistochemistry, electron microscopy, SDS-PAGE, and RNA-sequencing. Tissues derived from Arg719Cys heterozygotes displayed a deficient matrix, closely reflecting the human disease phenotype. Arg719Cys procollagen-II was excessively post-translationally modified and partially retained within the endoplasmic reticulum (ER), leading to ER distention. Notably, despite introduction of an aberrant cysteine residue-expected to engage redox-sensitive folding and quality control pathways-Arg719Cys procollagen-II was not detectably recognized by the ER proteostasis network. The resulting inability to mount a quality control response, including absent activation of the unfolded protein response, indicates a failure in cellular surveillance. As a result, malformed procollagen-II both accumulates intracellularly and is secreted, contributing to the deposition of a structurally compromised extracellular matrix that drives disease pathology. The iPSC-derived cartilage model presented here provides a genetically defined, expandable, and human-based system for dissecting mechanisms of failed proteostasis in collagenopathies. These findings shed light on the types of substitutions in procollagen that cells do or do not recognize, and underscore the therapeutic potential of targeting cellular surveillance and collagen quality control pathways in COL2A1-related disorders and beyond.

Authors: K. M. Yammine, S. Mirda Abularach, M. Xiong, S. Y. Kim, A. A. Bikovtseva, V. L. Butty, R. P. Schiavoni, J. F. Bateman, S. R. Lamande, M. D. Shoulders

Date Published: 3rd Sep 2025

Publication Type: Journal

PubMed ID: 40602718

DOI: 10.1016/j.jbc.2025.110436

Citation: J Biol Chem. 2025 Aug;301(8):110436. doi: 10.1016/j.jbc.2025.110436. Epub 2025 Jun 30.

Created: 25th Aug 2026 at 19:04