F Ter Heegde1, A P Luiz2, S Santana-Varela3, R Magnúsdóttir4, M Hopkinson5, Y Chang6, B Poulet7, R C Fowkes8, J N Wood9, C Chenu10. 1. Skeletal Biology Group, Comparative Biomedical Science, Royal Veterinary College, London NW1 0TU, UK; Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK. Electronic address: freijaterheegde@gmail.com. 2. Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK. Electronic address: a.luiz@ucl.ac.uk. 3. Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK. Electronic address: s.santana@ucl.ac.uk. 4. Skeletal Biology Group, Comparative Biomedical Science, Royal Veterinary College, London NW1 0TU, UK. Electronic address: rmagnusdottir@rvc.ac.uk. 5. Skeletal Biology Group, Comparative Biomedical Science, Royal Veterinary College, London NW1 0TU, UK. Electronic address: mhopkinson@rvc.ac.uk. 6. Research Office, Royal Veterinary College, London NW1 0TU, UK. Electronic address: ychang@rvc.ac.uk. 7. Muscoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L69 3BX, UK. Electronic address: b.poulet@liverpool.ac.uk. 8. Endocrine Signalling Group, Comparative Biomedical Science, Royal Veterinary College, London NW1 0TU, UK. Electronic address: rfowkes@rvc.ac.uk. 9. Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK. Electronic address: j.wood@ucl.ac.uk. 10. Skeletal Biology Group, Comparative Biomedical Science, Royal Veterinary College, London NW1 0TU, UK. Electronic address: cchenu@rvc.ac.uk.
Abstract
OBJECTIVE: In osteoarthritis (OA), the pain-structure relationship remains complex and poorly understood. Here, we used the mechanical joint loading (MJL) model of OA to investigate both knee pathology and nociceptive behaviour. DESIGN: MJL was used to induce OA in the right knees of 12-week-old male C57BL/6 mice (40 cycles, 9N, 3x/week for 2 weeks). Mechanical sensitivity thresholds and weight-bearing ratios were measured before loading and at weeks one, three and six post-loading. At these time points, separate groups of loaded and non-loaded mice (n = 12/group) were sacrificed, joints collected, and fur corticosterone levels measured. μCT analyses of subchondral bone integrity was performed before joint sections were prepared for nerve quantification, cartilage or synovium grading (scoring system from 0 to 6). RESULTS: Loaded mice showed increased mechanical hypersensitivity paired with altered weight-bearing. Initial ipsilateral cartilage lesions 1-week post-loading (1.8 ± 0.4) had worsened at weeks three (3.0 ± 0.6, CI = -1.8-0.6) and six (2.8 ± 0.4, CI = -1.6-0.4). This increase in lesion severity correlated with mechanical hypersensitivity development (correlation; 0.729, P = 0.0071). Loaded mice displayed increased synovitis (3.6 ± 0.5) compared to non-loaded mice (1.5 ± 0.5, CI = -2.2-0.3) 1-week post-loading which returned to normal by weeks three and six. Similarly, corticosterone levels were only increased at week one post-loading (0.21 ± 0.04 ng/mg) compared to non-loaded controls (0.14 ± 0.01 ng/mg, CI = -1.8-0.1). Subchondral bone integrity and nerve volume remained unchanged. CONCLUSIONS: Our data indicates that although the loading induces an initial stress reaction and local inflammation, these processes are not directly responsible for the nociceptive phenotype observed. Instead, MJL-induced allodynia is mainly associated with OA-like progression of cartilage lesions. Crown
OBJECTIVE: In osteoarthritis (OA), the pain-structure relationship remains complex and poorly understood. Here, we used the mechanical joint loading (MJL) model of OA to investigate both knee pathology and nociceptive behaviour. DESIGN: MJL was used to induce OA in the right knees of 12-week-old male C57BL/6 mice (40 cycles, 9N, 3x/week for 2 weeks). Mechanical sensitivity thresholds and weight-bearing ratios were measured before loading and at weeks one, three and six post-loading. At these time points, separate groups of loaded and non-loaded mice (n = 12/group) were sacrificed, joints collected, and fur corticosterone levels measured. μCT analyses of subchondral bone integrity was performed before joint sections were prepared for nerve quantification, cartilage or synovium grading (scoring system from 0 to 6). RESULTS: Loaded mice showed increased mechanical hypersensitivity paired with altered weight-bearing. Initial ipsilateral cartilage lesions 1-week post-loading (1.8 ± 0.4) had worsened at weeks three (3.0 ± 0.6, CI = -1.8-0.6) and six (2.8 ± 0.4, CI = -1.6-0.4). This increase in lesion severity correlated with mechanical hypersensitivity development (correlation; 0.729, P = 0.0071). Loaded mice displayed increased synovitis (3.6 ± 0.5) compared to non-loaded mice (1.5 ± 0.5, CI = -2.2-0.3) 1-week post-loading which returned to normal by weeks three and six. Similarly, corticosterone levels were only increased at week one post-loading (0.21 ± 0.04 ng/mg) compared to non-loaded controls (0.14 ± 0.01 ng/mg, CI = -1.8-0.1). Subchondral bone integrity and nerve volume remained unchanged. CONCLUSIONS: Our data indicates that although the loading induces an initial stress reaction and local inflammation, these processes are not directly responsible for the nociceptive phenotype observed. Instead, MJL-induced allodynia is mainly associated with OA-like progression of cartilage lesions. Crown
Authors: I M Berke; E Jain; B Yavuz; T McGrath; L Chen; M J Silva; G Mbalaviele; F Guilak; D L Kaplan; L A Setton Journal: Osteoarthritis Cartilage Date: 2020-11-24 Impact factor: 6.576
Authors: R Magnusdottir; S Gohin; F Ter Heegde; M Hopkinson; I F McNally; A Fisher; N Upton; A Billinton; C Chenu Journal: Osteoporos Int Date: 2021-06-02 Impact factor: 4.507