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

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 in...

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Autores principales: Staines, Katherine A., Ikpegbu, Ekele, Törnqvist, Anna E., Dillon, Scott, Javaheri, Behzad, Amin, Anish K., Clements, Dylan N., Buttle, David J., Pitsillides, Andrew A., Farquharson, Colin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661085/
https://www.ncbi.nlm.nih.gov/pubmed/31351471
http://dx.doi.org/10.1186/s12891-019-2731-9
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author Staines, Katherine A.
Ikpegbu, Ekele
Törnqvist, Anna E.
Dillon, Scott
Javaheri, Behzad
Amin, Anish K.
Clements, Dylan N.
Buttle, David J.
Pitsillides, Andrew A.
Farquharson, Colin
author_facet Staines, Katherine A.
Ikpegbu, Ekele
Törnqvist, Anna E.
Dillon, Scott
Javaheri, Behzad
Amin, Anish K.
Clements, Dylan N.
Buttle, David J.
Pitsillides, Andrew A.
Farquharson, Colin
author_sort Staines, Katherine A.
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12891-019-2731-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-66610852019-08-01 Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis Staines, Katherine A. Ikpegbu, Ekele Törnqvist, Anna E. Dillon, Scott Javaheri, Behzad Amin, Anish K. Clements, Dylan N. Buttle, David J. Pitsillides, Andrew A. Farquharson, Colin BMC Musculoskelet Disord Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12891-019-2731-9) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-27 /pmc/articles/PMC6661085/ /pubmed/31351471 http://dx.doi.org/10.1186/s12891-019-2731-9 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Staines, Katherine A.
Ikpegbu, Ekele
Törnqvist, Anna E.
Dillon, Scott
Javaheri, Behzad
Amin, Anish K.
Clements, Dylan N.
Buttle, David J.
Pitsillides, Andrew A.
Farquharson, Colin
Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis
title Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis
title_full Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis
title_fullStr Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis
title_full_unstemmed Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis
title_short Conditional deletion of E11/podoplanin in bone protects against load-induced osteoarthritis
title_sort conditional deletion of e11/podoplanin in bone protects against load-induced osteoarthritis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661085/
https://www.ncbi.nlm.nih.gov/pubmed/31351471
http://dx.doi.org/10.1186/s12891-019-2731-9
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