Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis

Karolina Kania, Fabio Colella, Anna H K Riemen, Hui Wang, Kenneth A Howard, Thomas Aigner, Francesco Dell'Accio, Terence D. Capellini, Anke J Roelofs, Cosimo de Bari* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Growth and Differentiation Factor 5 (GDF5) is a key risk locus for osteoarthritis (OA). However, little is known regarding regulation of Gdf5 expression following joint tissue damage. Here, we employed Gdf5-LacZ reporter mouse lines to assess the spatiotemporal activity of Gdf5 regulatory sequences in experimental OA following destabilisation of the medial meniscus (DMM) and after acute cartilage injury and repair. Gdf5 expression was upregulated in articular cartilage post-DMM, and was increased in human OA cartilage as determined by immunohistochemistry and microarray analysis. Gdf5 expression was also upregulated during cartilage repair in mice and was switched on in injured synovium in prospective areas of cartilage formation, where it inversely correlated with expression of the transcriptional co-factor Yes-associated protein (Yap). Indeed, overexpression of Yap suppressed Gdf5 expression in chondroprogenitors in vitro. Gdf5 expression in both mouse injury models required regulatory sequence downstream of Gdf5 coding exons. Our findings suggest that Gdf5 upregulation in articular cartilage and synovium is a generic response to knee injury that is dependent on downstream regulatory sequence and in progenitors is associated with chondrogenic specification. We propose a role for Gdf5 in tissue remodelling and repair after injury, which may partly underpin its association with OA risk.

Original languageEnglish
Article number157
JournalScientific Reports
Volume10
DOIs
Publication statusPublished - 13 Jan 2020

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Osteoarthritis
Cartilage
Joints
Tibial Meniscus
Synovial Membrane
Articular Cartilage
Wounds and Injuries
Growth Differentiation Factor 5
Knee Injuries
Microarray Analysis
Exons
Proteins
Up-Regulation
Immunohistochemistry

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Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis. / Kania, Karolina; Colella, Fabio; Riemen, Anna H K; Wang, Hui; Howard, Kenneth A; Aigner, Thomas; Dell'Accio, Francesco; Capellini, Terence D.; Roelofs, Anke J; de Bari, Cosimo (Corresponding Author).

In: Scientific Reports, Vol. 10, 157, 13.01.2020.

Research output: Contribution to journalArticle

Kania, Karolina ; Colella, Fabio ; Riemen, Anna H K ; Wang, Hui ; Howard, Kenneth A ; Aigner, Thomas ; Dell'Accio, Francesco ; Capellini, Terence D. ; Roelofs, Anke J ; de Bari, Cosimo. / Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis. In: Scientific Reports. 2020 ; Vol. 10.
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abstract = "Growth and Differentiation Factor 5 (GDF5) is a key risk locus for osteoarthritis (OA). However, little is known regarding regulation of Gdf5 expression following joint tissue damage. Here, we employed Gdf5-LacZ reporter mouse lines to assess the spatiotemporal activity of Gdf5 regulatory sequences in experimental OA following destabilisation of the medial meniscus (DMM) and after acute cartilage injury and repair. Gdf5 expression was upregulated in articular cartilage post-DMM, and was increased in human OA cartilage as determined by immunohistochemistry and microarray analysis. Gdf5 expression was also upregulated during cartilage repair in mice and was switched on in injured synovium in prospective areas of cartilage formation, where it inversely correlated with expression of the transcriptional co-factor Yes-associated protein (Yap). Indeed, overexpression of Yap suppressed Gdf5 expression in chondroprogenitors in vitro. Gdf5 expression in both mouse injury models required regulatory sequence downstream of Gdf5 coding exons. Our findings suggest that Gdf5 upregulation in articular cartilage and synovium is a generic response to knee injury that is dependent on downstream regulatory sequence and in progenitors is associated with chondrogenic specification. We propose a role for Gdf5 in tissue remodelling and repair after injury, which may partly underpin its association with OA risk.",
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note = "Funding: Arthritis Research UK (grants no. 20775, 19667, 20865, 21156); European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska Curie grant agreement no. 642414; Medical Research Council (grant MR/L022893/1); A.H.K.R. was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (grant no. WT 085664). The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.",
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AU - Aigner, Thomas

AU - Dell'Accio, Francesco

AU - Capellini, Terence D.

AU - Roelofs, Anke J

AU - de Bari, Cosimo

N1 - Funding: Arthritis Research UK (grants no. 20775, 19667, 20865, 21156); European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska Curie grant agreement no. 642414; Medical Research Council (grant MR/L022893/1); A.H.K.R. was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (grant no. WT 085664). The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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