Background:Cartilage defects in the joints are reported in 61% of all arthroscopies1&2. The size of the cartilage repair market is estimated to be $2.195 million by 20253. Cartilage defects can evolve into osteoarthritis, in which abnormal load results in cartilage breakdown, joint pain and reduced mobility. Osteoarthritis is the leading cause of permanent disability and absenteeism and affects up to 1/3 of the people over 60yrs. In western countries osteoarthritis costs 1.5-2% of the GDP4. Joint replacement with a prosthesis restores some degree of independence but in up to 20% of patients it does not meet expectations 5 and has a limited life span. There is no pharmacological intervention that arrests or reverts the course of osteoarthritis, despite the desperate need.We previously published that agrin plays an important role in cartilage homeostasis6. The addition of agrin to chondrocytes in vivo resulted in enhanced cartilage formation, suggesting a potential role for agrin in cartilage repair.Objectives:Investigate the potential of agrin for use in cartilage repair.Methods:Critical size osteochondral defects were generated in mice and sheep and injected intraarticularly with type I collagen gel containing agrin or vehicle. Animals were monitored for 8 weeks or 6 months respectively. MicroCT, histological analysis, qPCR, linage tracking, reporter assays, chondrogenesis assay, immunohistochemistry were performed.Results:A single intraarticular administration of agrin induced regeneration of critical-size osteochondral defects in mice, restoring the tissue architecture and bone-cartilage interface. Agrin stem cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signalling, induced GDF5 expression and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, agrin treatment resulted in regeneration of bone and cartilage, which promoted increased ambulatory activity.Conclusion:Agrin orchestrates repair morphogenesis at the joint surface by modulating multiple signalling pathways, supporting the therapeutic use of agrin for joint surface regeneration.References:[1]Curl, W. W. et al. Cartilage injuries: a review of 31,516 knee arthroscopies. Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc. 13, 456–460 (1997).[2]Hjelle, K., Solheim, E., Strand, T., Muri, R. & Brittberg, M. Articular cartilage defects in 1,000 knee arthroscopies. Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc. 18, 730–734 (2002).[3]Cartilage Repair Market Size, Share, Industry Analysis 2018-2025 | AMR. Allied Market Research https://www.alliedmarketresearch.com/cartilage-repair-market.[4]Hiligsmann, M. et al. Health economics in the field of osteoarthritis: an expert’s consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Semin. Arthritis Rheum. 43, 303–313 (2013).[5]Dieppe, P., Lim, K. & Lohmander, S. Who should have knee joint replacement surgery for osteoarthritis? Int. J. Rheum. Dis. 14, 175–180 (2011).[6]Eldridge, S., et al. Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in vivo. Annals of the rheumatic diseases 75 (6), 1228-1235 (2016).Acknowledgements:We thank the technical staff in the ARM Lab and Staff at the University of Aberdeen’s Animal Facility and Microscopy and Histology Facility for support. Funding: We gratefully acknowledge funding support of this work by the MRC (MR/L022893/1, MR/N010973/1,and MR/P026362/1), Versus Arthritis (19667, 21515, 20886, and 21621), Rosetrees Trust (A1205), the Medical College of St Bartholomew’s Hospital Trust, and the William Harvey Research Foundation.Disclosure of Interests:Suzanne Eldridge: None declared, Aida Barawi: None declared, Hui Wang: None declared, Anke Roelofs: None declared, Magdalena Kaneva: None declared, Zeyu Guan: None declared, Helen Lydon: None declared, Bethan Thomas: None declared, Anne-Sophie Thorup: None declared, Beatriz F Fernandez: None declared, Sara Caxaria: None declared, Danielle Strachan: None declared, Ahmed Ali: None declared, Kanatheepan Shanmuganathan: None declared, Costantino Pitzalis: None declared, James Whiteford: None declared, Fran Henson: None declared, Andrew McCaskie: None declared, Cosimo De Bari: None declared, Francesco Dell’Accio Consultant of: F.D. has received consultancy fees from Samumed and UCB.
Articular Cartilage Repair of the Knee in Children and Adolescents
