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

doi:10.1038/s41598-019-57011-8

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 journal › Article › peer-review

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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.

Original language	English
Article number	157
Number of pages	11
Journal	Scientific Reports
Volume	10
DOIs	https://doi.org/10.1038/s41598-019-57011-8
Publication status	Published - 13 Jan 2020

Bibliographical 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.

Keywords

ALLELIC EXPRESSION
ARTICULAR-CARTILAGE FORMATION
BRACHYPODISM
GROWTH
MICE
MORPHOGENESIS
MUTATIONS
PROTEINS
SUSCEPTIBILITY
SYNOVIAL JOINT

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Cite this

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title = "Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis",

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.",

keywords = "ALLELIC EXPRESSION, ARTICULAR-CARTILAGE FORMATION, BRACHYPODISM, GROWTH, MICE, MORPHOGENESIS, MUTATIONS, PROTEINS, SUSCEPTIBILITY, SYNOVIAL JOINT",

author = "Karolina Kania and Fabio Colella and Riemen, {Anna H K} and Hui Wang and Howard, {Kenneth A} and Thomas Aigner and Francesco Dell'Accio and Capellini, {Terence D.} and Roelofs, {Anke J} and {de Bari}, Cosimo",

note = "Funding: Arthritis Research UK (grants no. 20775, 19667, 20865, 21156); European Union{\textquoteright}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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doi = "10.1038/s41598-019-57011-8",

language = "English",

volume = "10",

journal = "Scientific Reports",

issn = "2045-2322",

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AU - Kania, Karolina

AU - Colella, Fabio

AU - Riemen, Anna H K

AU - Wang, Hui

AU - Howard, Kenneth A

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.

PY - 2020/1/13

Y1 - 2020/1/13

N2 - 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.

AB - 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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KW - ARTICULAR-CARTILAGE FORMATION

KW - BRACHYPODISM

KW - GROWTH

KW - MICE

KW - MORPHOGENESIS

KW - MUTATIONS

KW - PROTEINS

KW - SUSCEPTIBILITY

KW - SYNOVIAL JOINT

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U2 - 10.1038/s41598-019-57011-8

DO - 10.1038/s41598-019-57011-8

M3 - Article

C2 - 31932746

SN - 2045-2322

VL - 10

JO - Scientific Reports

JF - Scientific Reports

M1 - 157

ER -

Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis

Abstract

Bibliographical note

Keywords

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Cosimo De Bari

Anke Roelofs

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Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis

Abstract

Bibliographical note

Keywords

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Cosimo De Bari

Anke Roelofs

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