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

Journal article
Authors K. A. Staines
E. Ikpegbu
Anna E Törnqvist
S. Dillon
B. Javaheri
A. K. Amin
D. N. Clements
D. J. Buttle
A. A. Pitsillides
C. Farquharson
Published in Bmc Musculoskeletal Disorders
Volume 20
Issue 1
ISSN 1471-2474
Publication year 2019
Published at Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Language en
Links dx.doi.org/10.1186/s12891-019-2731-...
Keywords Osteocytes, Subchondral bone, Osteoarthritis, E11, podoplanin, subchondral bone, proteasome, expression, osteocyte, inhibition, cartilage, strain, type-2, Orthopedics, Rheumatology
Subject categories Rheumatology and Autoimmunity

Abstract

BackgroundSubchondral 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.MethodsWe 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 (1mg/kg/day) for 8weeks 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.ResultsOur 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.ConclusionsOverall, 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.

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