iScience (Jul 2023)
Ablation of collagen XII disturbs joint extracellular matrix organization and causes patellar subluxation
- Mengjie Zhu,
- Fabian Metzen,
- Mark Hopkinson,
- Janina Betz,
- Juliane Heilig,
- Jassi Sodhi,
- Thomas Imhof,
- Anja Niehoff,
- David E. Birk,
- Yayoi Izu,
- Marcus Krüger,
- Andrew A. Pitsillides,
- Janine Altmüller,
- Gerjo J.V.M. van Osch,
- Volker Straub,
- Gudrun Schreiber,
- Mats Paulsson,
- Manuel Koch,
- Bent Brachvogel
Affiliations
- Mengjie Zhu
- Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Institute for Dental Research and Oral Musculoskeletal Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Biochemistry, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
- Fabian Metzen
- Institute for Dental Research and Oral Musculoskeletal Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Biochemistry, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
- Mark Hopkinson
- Skeletal Biology Group, Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London, UK
- Janina Betz
- Institute for Dental Research and Oral Musculoskeletal Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Biochemistry, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
- Juliane Heilig
- Institute of Biomechanics & Orthopaedics, German Sport University Cologne, Cologne, Germany; Center for Musculoskeletal Biomechanics (CCMB), Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
- Jassi Sodhi
- John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle, UK
- Thomas Imhof
- Institute for Dental Research and Oral Musculoskeletal Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Biochemistry, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
- Anja Niehoff
- Institute of Biomechanics & Orthopaedics, German Sport University Cologne, Cologne, Germany; Center for Musculoskeletal Biomechanics (CCMB), Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany
- David E. Birk
- College of Medicine, University of South Florida, Morsani, Tampa, FL, USA
- Yayoi Izu
- Department of Veterinary Medicine, Okayama University of Science, Ehime, Japan
- Marcus Krüger
- Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Andrew A. Pitsillides
- Skeletal Biology Group, Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London, UK
- Janine Altmüller
- Cologne Center for Genomics, University of Cologne, Cologne, Germany; Berlin Institute of Health at Charité, Core Facility Genomics, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Gerjo J.V.M. van Osch
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Department of Otorhinolaryngology, Erasmus MC, University Medical Center, CN Rotterdam, the Netherlands
- Volker Straub
- John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle, UK
- Gudrun Schreiber
- Department of Neuropediatrics, Klinikum Kassel, Kassel, Germany
- Mats Paulsson
- Center for Biochemistry, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Manuel Koch
- Institute for Dental Research and Oral Musculoskeletal Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Biochemistry, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Corresponding author
- Bent Brachvogel
- Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Biochemistry, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 7
p. 107225
Abstract
Summary: Collagen XII, belonging to the fibril-associated collagens, is a homotrimeric secreted extracellular matrix (ECM) protein encoded by the COL12A1 gene. Mutations in the human COL12A1 gene cause an Ehlers-Danlos/myopathy overlap syndrome leading to skeletal abnormalities and muscle weakness. Here, we studied the role of collagen XII in joint pathophysiology by analyzing collagen XII deficient mice and human patients. We found that collagen XII is widely expressed across multiple connective tissue of the developing joint. Lack of collagen XII in mice destabilizes tendons and the femoral trochlear groove to induce patellar subluxation in the patellofemoral joint. These changes are associated with an ECM damage response in tendon and secondary quadriceps muscle degeneration. Moreover, patellar subluxation was also identified as a clinical feature of human patients with collagen XII deficiency. The results provide an explanation for joint hyperlaxity in mice and human patients with collagen XII deficiency.
