Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784569924013785088 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8451793 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT deshmukhvishal sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT seotim sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT ogreenalyssal sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT ibanezmaureen sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT hofilenabrian sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT kcsunil sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT stewartjoshua sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT dellamaryluis sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT chiukevin sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT ghiasabdullah sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT barrogacharlene sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT kennedysarah sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT tambiahjeyanesh sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT hoodjohn sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy AT yaziciyusuf sm04755asmallmoleculeinhibitorofthewntpathwayasapotentialtopicaltreatmentfortendinopathy |