Functional Loss of Terminal Complement Complex Protects Rabbits from Injury-Induced Osteoarthritis on Structural and Cellular Level

Author:

Riegger Jana1ORCID,Joos Helga1,Möhler Valentin1,Leucht Frank2,Rading Katrin3,Kubisch Christian3,Ignatius Anita4ORCID,Huber-Lang Markus5,Brenner Rolf E.1

Affiliation:

1. Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, University of Ulm, 89081 Ulm, Germany

2. Department of Orthopedics, University of Ulm, 89081 Ulm, Germany

3. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

4. Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, 89081 Ulm, Germany

5. Institute of Clinical and Experimental Trauma-Immunology, University Hospital Ulm, 89081 Ulm, Germany

Abstract

The terminal complement complex (TCC) has been described as a potential driver in the pathogenesis of posttraumatic osteoarthritis (PTOA). However, sublytic TCC deposition might also play a crucial role in bone development and regeneration. Therefore, we elucidated the effects of TCC on joint-related tissues using a rabbit PTOA model. In brief, a C6-deficient rabbit breed was characterized on genetic, protein, and functional levels. Anterior cruciate ligament transection (ACLT) was performed in C6-deficient (C6−/−) and C6-sufficient (C6+/−) rabbits. After eight weeks, the progression of PTOA was determined histologically. Moreover, the structure of the subchondral bone was evaluated by µCT analysis. C6 deficiency could be attributed to a homozygous 3.6 kb deletion within the C6 gene and subsequent loss of the C5b binding site. Serum from C6−/− animals revealed no hemolytic activity. After ACLT surgery, joints of C6−/− rabbits exhibited significantly lower OA scores, including reduced cartilage damage, hypocellularity, cluster formation, and osteophyte number, as well as lower chondrocyte apoptosis rates and synovial prostaglandin E2 levels. Moreover, ACLT surgery significantly decreased the trabecular number in the subchondral bone of C6−/− rabbits. Overall, the absence of TCC protected from injury-induced OA progression but had minor effects on the micro-structure of the subchondral bone.

Funder

European Social Fund

Ministry of Science, Research and Arts Baden-Württemberg

Publisher

MDPI AG

Subject

Molecular Biology,Biochemistry

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