Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment.

Autor: Deshmukh V; Samumed, LLC, San Diego, CA, USA. Electronic address: vishal@samumed.com., O'Green AL; Samumed, LLC, San Diego, CA, USA. Electronic address: alyssao@samumed.com., Bossard C; Samumed, LLC, San Diego, CA, USA. Electronic address: carine@samumed.com., Seo T; Samumed, LLC, San Diego, CA, USA. Electronic address: tims@samumed.com., Lamangan L; Samumed, LLC, San Diego, CA, USA. Electronic address: lisa@samumed.com., Ibanez M; Samumed, LLC, San Diego, CA, USA. Electronic address: maureen@samumed.com., Ghias A; Samumed, LLC, San Diego, CA, USA. Electronic address: abdullah@samumed.com., Lai C; Samumed, LLC, San Diego, CA, USA. Electronic address: carolyn@samumed.com., Do L; Samumed, LLC, San Diego, CA, USA. Electronic address: long@samumed.com., Cho S; Samumed, LLC, San Diego, CA, USA. Electronic address: shawn@samumed.com., Cahiwat J; Samumed, LLC, San Diego, CA, USA. Electronic address: joec@samumed.com., Chiu K; Samumed, LLC, San Diego, CA, USA. Electronic address: kevin@samumed.com., Pedraza M; Samumed, LLC, San Diego, CA, USA. Electronic address: melinda@samumed.com., Anderson S; Samumed, LLC, San Diego, CA, USA. Electronic address: scotta@samumed.com., Harris R; Samumed, LLC, San Diego, CA, USA. Electronic address: rodney@samumed.com., Dellamary L; Samumed, LLC, San Diego, CA, USA. Electronic address: luis@samumed.com., Kc S; Samumed, LLC, San Diego, CA, USA. Electronic address: sunil@samumed.com., Barroga C; Samumed, LLC, San Diego, CA, USA. Electronic address: charlene@samumed.com., Melchior B; Samumed, LLC, San Diego, CA, USA. Electronic address: benoit@semumed.com., Tam B; Formerly Samumed, LLC, USA. Electronic address: byytam@sbcglobal.net., Kennedy S; Samumed, LLC, San Diego, CA, USA. Electronic address: sarahk@samumed.com., Tambiah J; Samumed, LLC, San Diego, CA, USA. Electronic address: jeymi@samumed.com., Hood J; Formerly Samumed, LLC, USA. Electronic address: hoodpharmaceuticals@gmail.com., Yazici Y; Samumed, LLC, San Diego, CA, USA. Electronic address: yusuf@samumed.com.
Jazyk: angličtina
Zdroj: Osteoarthritis and cartilage [Osteoarthritis Cartilage] 2019 Sep; Vol. 27 (9), pp. 1347-1360. Date of Electronic Publication: 2019 May 25.
DOI: 10.1016/j.joca.2019.05.006
Abstrakt: Objectives: Wnt pathway upregulation contributes to knee osteoarthritis (OA) through osteoblast differentiation, increased catabolic enzymes, and inflammation. The small-molecule Wnt pathway inhibitor, lorecivivint (SM04690), which previously demonstrated chondrogenesis and cartilage protection in an animal OA model, was evaluated to elucidate its mechanism of action.
Design: Biochemical assays measured kinase activity. Western blots measured protein phosphorylation in human mesenchymal stem cells (hMSCs), chondrocytes, and synovial fibroblasts. siRNA knockdown effects in hMSCs and BEAS-2B cells on Wnt pathway, chondrogenic genes, and LPS-induced inflammatory cytokines was measured by qPCR. In vivo anti-inflammation, pain, and function were evaluated following single intra-articular (IA) lorecivivint or vehicle injection in the monosodium iodoacetate (MIA)-induced rat OA model.
Results: Lorecivivint inhibited intranuclear kinases CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Lorecivivint inhibited CLK2-mediated phosphorylation of serine/arginine-rich (SR) splicing factors and DYRK1A-mediated phosphorylation of SIRT1 and FOXO1. siRNA knockdowns identified a role for CLK2 and DYRK1A in Wnt pathway modulation without affecting β-catenin with CLK2 inhibition inducing early chondrogenesis and DYRK1A inhibition enhancing mature chondrocyte function. NF-κB and STAT3 inhibition by lorecivivint reduced inflammation. DYRK1A knockdown was sufficient for anti-inflammatory effects, while combined DYRK1A/CLK2 knockdown enhanced this effect. In the MIA model, lorecivivint inhibited production of inflammatory cytokines and cartilage degradative enzymes, resulting in increased joint cartilage, decreased pain, and improved weight-bearing function.
Conclusions: Lorecivivint inhibition of CLK2 and DYRK1A suggested a novel mechanism for Wnt pathway inhibition, enhancing chondrogenesis, chondrocyte function, and anti-inflammation. Lorecivivint shows potential to modify structure and improve symptoms of knee OA.
(Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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