Targeting senescence and inflammation in chronic destructive TNF-driven joint pathology

Nikolaos I Vlachogiannis; Konstantinos Evangelou; Lydia Ntari; Christoforos Nikolaou; Maria C Denis; Niki Karagianni; Dimitris Veroutis; Vassilis Gorgoulis; George Kollias; Petros P Sfikakis

doi:10.1016/j.mad.2023.111856

Targeting senescence and inflammation in chronic destructive TNF-driven joint pathology

Mech Ageing Dev. 2023 Sep:214:111856. doi: 10.1016/j.mad.2023.111856. Epub 2023 Aug 7.

Affiliations

¹ First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece; Department of Physiology, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece. Electronic address: nivlachogiannis@gmail.com.
² Molecular Carcinogenesis Group, Department of Histology and Embryology, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece.
³ Biomedcode Hellas SA, Vari, Greece.
⁴ Institute for Bioinnovation, Biomedical Sciences Research Center (B.S.R.C.) "Alexander Fleming", 16672 Vari, Greece.
⁵ Molecular Carcinogenesis Group, Department of Histology and Embryology, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece; Biomedical Research Foundation, Academy of Athens, Athens, Greece; Ninewells Hospital and Medical School, University of Dundee, Dundee, UK; Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Faculty of Health and Medical Sciences, University of Surrey, UK.
⁶ Department of Physiology, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece; Institute for Bioinnovation, Biomedical Sciences Research Center (B.S.R.C.) "Alexander Fleming", 16672 Vari, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
⁷ First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Postgraduate Medical Studies in Geriatric Syndromes and Physiology of Aging, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

PMID: 37558168
DOI: 10.1016/j.mad.2023.111856

Abstract

We had shown that administration of the senolytic Dasatinib abolishes arthritis in the human TNF transgenic mouse model of chronic destructive arthritis when given in combination with a sub-therapeutic dose of the anti-TNF mAb Infliximab (1 mg/kg). Herein, we found that while the number of senescent chondrocytes (GL13⁺/Ki67^-), assessed according to guideline algorithmic approaches, was not affected by either Dasatinib or sub-therapeutic Infliximab monotherapies, their combination reduced senescent chondrocytes by 50 %, which was comparable to levels observed with therapeutic Infliximab monotherapy (10 mg/kg). This combination therapy also reduced the expression of multiple factors of senescence-associated secretory phenotype in arthritic joints. Studies to elucidate the interplay of inflammation and senescence may help in optimizing treatment strategies also for age-related pathologies characterized by chronic low-grade joint inflammation.

Keywords: Dasatinib; Inflammatory arthritis; SASP; Senescence; Senolytic; TNF-α.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis*
Cellular Senescence*
Dasatinib / pharmacology
Humans
Inflammation
Infliximab / pharmacology
Mice
Mice, Transgenic
Tumor Necrosis Factor Inhibitors / pharmacology

Substances

Dasatinib
Infliximab
Tumor Necrosis Factor Inhibitors