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

doi:10.1016/j.isci.2023.107225

Ablation of collagen XII disturbs joint extracellular matrix organization and causes patellar subluxation

iScience. 2023 Jun 28;26(7):107225. doi: 10.1016/j.isci.2023.107225. eCollection 2023 Jul 21.

Authors

Mengjie Zhu^{1

2

3}, Fabian Metzen^{2

3}, Mark Hopkinson⁴, Janina Betz^{2

3}, Juliane Heilig^{5

6}, Jassi Sodhi⁷, Thomas Imhof^{2

3}, Anja Niehoff^{5

6}, David E Birk⁸, Yayoi Izu⁹, Marcus Krüger^{10

11}, Andrew A Pitsillides⁴, Janine Altmüller^{12

13

14}, Gerjo J V M van Osch^{15

16}, Volker Straub⁷, Gudrun Schreiber¹⁷, Mats Paulsson^{3

11}, Manuel Koch^{2

3

11}, Bent Brachvogel^{1

3}

Affiliations

¹ Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
² Institute for Dental Research and Oral Musculoskeletal Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³ Center for Biochemistry, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁴ Skeletal Biology Group, Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London, UK.
⁵ Institute of Biomechanics & Orthopaedics, German Sport University Cologne, Cologne, Germany.
⁶ Center for Musculoskeletal Biomechanics (CCMB), Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷ 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.
⁸ College of Medicine, University of South Florida, Morsani, Tampa, FL, USA.
⁹ Department of Veterinary Medicine, Okayama University of Science, Ehime, Japan.
¹⁰ Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹¹ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
¹² Cologne Center for Genomics, University of Cologne, Cologne, Germany.
¹³ Berlin Institute of Health at Charité, Core Facility Genomics, Berlin, Germany.
¹⁴ Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
¹⁵ Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
¹⁶ Department of Otorhinolaryngology, Erasmus MC, University Medical Center, CN Rotterdam, the Netherlands.
¹⁷ Department of Neuropediatrics, Klinikum Kassel, Kassel, Germany.

Abstract

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.

Keywords: Biological sciences; Health sciences; Molecular biology.