Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis

BMC Musculoskeletal Disorders

Andrew A. Pitsillides¹  Behzad Javaheri¹  David J. Buttle²  Anish K. Amin³  Ekele Ikpegbu⁴  Anna E. Törnqvist⁵  Scott Dillon⁶  Colin Farquharson⁶  Dylan N. Clements⁶  Katherine A. Staines⁷ 

[1] Comparative Biomedical Sciences, Royal Veterinary College;Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield;Department of Orthopaedic and Trauma Surgery, Royal Infirmary of Edinburgh, NHS Lothian;Michael Okpara University of Agriculture;Rheumatology and Bone Diseases Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh;Roslin Institute and R(D)SVS, The University of Edinburgh;School of Applied Sciences, Edinburgh Napier University;

关键词: Osteocytes;    Subchondral bone;    Osteoarthritis;    E11/podoplanin;   

DOI  :  10.1186/s12891-019-2731-9

来源: DOAJ

【 摘 要 】

Abstract Background Subchondral bone (SCB) thickening is one of the earliest detectable changes in osteoarthritic joints and is considered a potential trigger for subsequent articular cartilage degeneration. In this manuscript, we examine whether disruption to the SCB osteocyte network contributes to the initiation and pathogenesis of osteoarthritis. Methods We examined expression patterns of the glycoprotein E11/podoplanin by immunohistochemical labelling in murine, human and canine osteoarthritis models. We also examined the effects of twice-weekly administration of Bortezomib, a proteasome inhibitor which stabilises osteocyte E11 levels, to C57/BL6 wild-type male mice (1 mg/kg/day) for 8 weeks after surgical destabilisation of the medial meniscus. By inducing osteoarthritis-like changes in the right knee joint of 12-week-old male E11 hypomorphic mice (and corresponding controls) using a post-traumatic joint loading model, we also investigated whether a bone-specific E11 deletion in mice increases joint vulnerability to osteoarthritis. Articular cartilage degradation and osteophyte formation were assessed by histology and in line with the OARSI grading system. Results Our studies reveal increased E11 expression in osteocytes of human and canine osteoarthritic SCB. We found that Bortezomib administration had no effect on surgically-induced osteoarthritis, potentially due to a lack of the expected stabilisation of E11 in the SCB. We also found, in concordance with our previous work, wild-type mice exhibited significant load-induced articular cartilage lesions on the lateral femoral condyle (p < 0.01) and osteophyte formation. In contrast, E11 hypomorphic mice did not develop osteophytes or any corresponding articular lesions. Conclusions Overall, these data suggest that an intact osteocyte network in the SCB contributes to the development of mechanically-driven osteoarthritis. Further, the data presented here indicate that the molecular pathways that preserve the osteocyte network, such as those driven by E11, may be targeted to limit osteoarthritis pathogenesis.

【 授权许可】

Unknown