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SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy

The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small‐molecule Wnt...

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Autores principales: Deshmukh, Vishal, Seo, Tim, O'Green, Alyssa L., Ibanez, Maureen, Hofilena, Brian, KC, Sunil, Stewart, Joshua, Dellamary, Luis, Chiu, Kevin, Ghias, Abdullah, Barroga, Charlene, Kennedy, Sarah, Tambiah, Jeyanesh, Hood, John, Yazici, Yusuf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451793/
https://www.ncbi.nlm.nih.gov/pubmed/33104243
http://dx.doi.org/10.1002/jor.24898
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author Deshmukh, Vishal
Seo, Tim
O'Green, Alyssa L.
Ibanez, Maureen
Hofilena, Brian
KC, Sunil
Stewart, Joshua
Dellamary, Luis
Chiu, Kevin
Ghias, Abdullah
Barroga, Charlene
Kennedy, Sarah
Tambiah, Jeyanesh
Hood, John
Yazici, Yusuf
author_facet Deshmukh, Vishal
Seo, Tim
O'Green, Alyssa L.
Ibanez, Maureen
Hofilena, Brian
KC, Sunil
Stewart, Joshua
Dellamary, Luis
Chiu, Kevin
Ghias, Abdullah
Barroga, Charlene
Kennedy, Sarah
Tambiah, Jeyanesh
Hood, John
Yazici, Yusuf
author_sort Deshmukh, Vishal
collection PubMed
description The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small‐molecule Wnt pathway inhibitor, for the treatment of tendinopathy using in vitro assays and animal models. In vitro, SM04755 decreased Wnt pathway activity, induced tenocyte differentiation, and inhibited catabolic enzymes and pro‐inflammatory cytokines in human mesenchymal stem cells, rat tendon‐derived stem cells, and human peripheral blood mononuclear cells. Evaluation of the mechanism of action of SM04755 by biochemical profiling and computational modeling identified CDC‐like kinase 2 (CLK2) and dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A) as molecular targets. CLK and DYRK1A inhibition by siRNA knockdown or pharmacological inhibition induced tenocyte differentiation and reduced tenocyte catabolism. In vivo, topically applied SM04755 showed therapeutically relevant exposure in tendons with low systemic exposure and no detectable toxicity in rats. Moreover, SM04755 showed reduced tendon inflammation and evidence of tendon regeneration, decreased pain, and improved weight‐bearing function in rat collagenase‐induced tendinopathy models compared with vehicle control. Together, these data demonstrate that CLK2 and DYRK1A inhibition by SM04755 resulted in Wnt pathway inhibition, enhanced tenocyte differentiation and protection, and reduced inflammation. SM04755 has the potential to benefit symptoms and modify disease processes in tendinopathy.
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spelling pubmed-84517932021-09-27 SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy Deshmukh, Vishal Seo, Tim O'Green, Alyssa L. Ibanez, Maureen Hofilena, Brian KC, Sunil Stewart, Joshua Dellamary, Luis Chiu, Kevin Ghias, Abdullah Barroga, Charlene Kennedy, Sarah Tambiah, Jeyanesh Hood, John Yazici, Yusuf J Orthop Res RESEARCH ARTICLES The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small‐molecule Wnt pathway inhibitor, for the treatment of tendinopathy using in vitro assays and animal models. In vitro, SM04755 decreased Wnt pathway activity, induced tenocyte differentiation, and inhibited catabolic enzymes and pro‐inflammatory cytokines in human mesenchymal stem cells, rat tendon‐derived stem cells, and human peripheral blood mononuclear cells. Evaluation of the mechanism of action of SM04755 by biochemical profiling and computational modeling identified CDC‐like kinase 2 (CLK2) and dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A) as molecular targets. CLK and DYRK1A inhibition by siRNA knockdown or pharmacological inhibition induced tenocyte differentiation and reduced tenocyte catabolism. In vivo, topically applied SM04755 showed therapeutically relevant exposure in tendons with low systemic exposure and no detectable toxicity in rats. Moreover, SM04755 showed reduced tendon inflammation and evidence of tendon regeneration, decreased pain, and improved weight‐bearing function in rat collagenase‐induced tendinopathy models compared with vehicle control. Together, these data demonstrate that CLK2 and DYRK1A inhibition by SM04755 resulted in Wnt pathway inhibition, enhanced tenocyte differentiation and protection, and reduced inflammation. SM04755 has the potential to benefit symptoms and modify disease processes in tendinopathy. John Wiley and Sons Inc. 2020-11-18 2021-09 /pmc/articles/PMC8451793/ /pubmed/33104243 http://dx.doi.org/10.1002/jor.24898 Text en © 2020 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle RESEARCH ARTICLES
Deshmukh, Vishal
Seo, Tim
O'Green, Alyssa L.
Ibanez, Maureen
Hofilena, Brian
KC, Sunil
Stewart, Joshua
Dellamary, Luis
Chiu, Kevin
Ghias, Abdullah
Barroga, Charlene
Kennedy, Sarah
Tambiah, Jeyanesh
Hood, John
Yazici, Yusuf
SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy
title SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy
title_full SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy
title_fullStr SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy
title_full_unstemmed SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy
title_short SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy
title_sort sm04755, a small‐molecule inhibitor of the wnt pathway, as a potential topical treatment for tendinopathy
topic RESEARCH ARTICLES
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451793/
https://www.ncbi.nlm.nih.gov/pubmed/33104243
http://dx.doi.org/10.1002/jor.24898
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