IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis

Abstract

Conflict of interest: DZ is an inventor of a pending patent application for BCL-xL inhibitors and targeted senolytic agents for age-related diseases (Compounds that induce degradation of anti-apoptotic BCL-2 family proteins and the uses thereof, no. US20190135801). DZ and JC are cofounders, advisors for, and shareholders of Unity Biotechnology, which develops senolytic agents. JHE is an equity holder of Unity Biotechnology, receives patent royalties through Johns Hopkins University School of Medicine (Unit dose of a cis-imidazoline for treating an osteoarthritic joint by removing senescent cells, no. US9849128B2), and is a founder and equity holder of Aegeria Soft Tissue (AST). DMP is a consultant for Aduro Biotech, Amgen, Astra Zeneca, Bayer, DNAtrix, Dynavax Technologies, Ervaxx, FLX Bio, Janssen, Merck, and Rock Springs Capital. DMP also provides research support and consulting to Compugen and Bristol Myers Squibb and receives patent royalties through Johns Hopkins University School of Medicine. DMP is on the scientific advisory board of Camden Nexus II; is on the board of directors of and owns stock in Dracen Pharmaceuticals, Five Prime Therapeutics, and WindMIL Therapeutics; is a consultant for Immunomic Therapeutics and Tizona Therapeutics; has equity and patent royalties through Johns Hopkins University School of Medicine (Use of multivalent chimeric peptide-loaded, MHC/lg molecules to detect, activate or suppress antigen-specific, T cell-dependent immune responses; no. PCT/US98/18909; Manipulation of regulatory T cells using LAG-3 antibodies, genes, agonists and antagonists, no. PCT/US04/006133; Microsatellite instability as a pharmacogenomic marker of therapeutic response to immune checkpoint inhibition, no. PCT/US2015/060331; Immune checkpoint chimeric antigen receptors (CAR) therapy, no. PCT/US2016/040010; Marrow infiltrating lymphocytes (MILs) as a source of T-cells for chimeric antigen receptor (CAR) therapy, no. PCT/US2016/041521; Combination of immunotherapy with local chemotherapy for the treatment of malignancies, no. PCT/US2016/028861; Use of SON-211 and Ontak as a regulatory T cell targeted cancer immunotherapy in combination with anti-PD-1 therapy for the treatment of cancer, no. PCT/US2019/020959); and has founder equity in Potenza Therapeutics and Trieza Therapeutics.

An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

“…These studies demonstrate that, like TNF-α or IL-β, IL-17 is strongly capable of enhancing inflammation and causing catabolic effects that lead to degeneration of articular cartilage; and that potentiating effects of cytokine combinations with IL-17 surpass those of individual cytokines. This review, in the context of PTOA of the knee, as well as others reviews, suggest that IL-17 is a crucial pathogenic molecule in local and systemic disease pathogenesis in many types of disease tissues and that IL-17 signaling may promote chronic disease development [ 185 , 186 , 187 , 188 , 189 ] emphasizing the need for further mechanistic IL-17 studies in various contexts.…”

“…DAMPs are present in normal healthy chondrocytes, but increased in OA [ 260 ]. DAMPs also induce cellular senescence and are produced by senescent cells (SnCs) and, like DAMPs, cellular senescence has been suggested to contribute to low grade chronic systemic inflammation in OA [ 261 , 262 , 263 ] and in PTOA [ 189 , 264 , 265 , 266 ]. Senescent cells (SnCs) increase in response to aging but also increase upon injury, stress and inflammation and, thus, are relevant to trauma-related pathologies.…”

“…SnCs release a wide-range of proteins, including DAMPs, as well as pro-inflammatory cytokines, MMPs, and chemokines, including those factors shown in Figure 1 that were significantly increased following trauma to the knee joint, such as IL-6, IL-1, TNF-α and MMP-3. Moreover, inflammatory cytokines present after knee trauma, such as IL-1β, TNF-α and IL-17, drive chondrocytes [ 267 ] and fibroblasts [ 189 ] towards a senescent phenotype.…”

“…As with DAMP-PRR signaling, SnCs are needed for normal healing in acute inflammation and their presence limits fibrosis during tissue repair [ 268 , 269 ]. On the other hand, SnCs are also capable of promoting OA disease progression when transplanted into normal knee healthy joints of mature adult mice equivalent in age to 20–30-year-old humans [ 261 ] and in young animals in PTOA knee models [ 189 , 264 ]. Thus, ACLT injury induced senescence in both young and aged animals.…”

Apremilast prevents IL‑17‑induced cellular senescence in ATDC5 chondrocytes mediated by SIRT1

“…However, IL-17 inhibition appears to be effective in the treatment of psoriasis (43). Notably, a recent study revealed that intra-articular injection of an IL-17-neutralizing antibody reduced joint degeneration in aging OA mice (44). However, IL-17 inhibition has not been trialed in the treatment of OA in patients.…”