Introduction

The multifaceted nature of osteoarthritis (OA) places high demands on potential therapeutics, which ideally should be capable of eliciting multifactorial responses to effectively treat this complex disease. Current clinical therapies only address the pain of OA disease and are not yet able to perform disease modifying activity and rebuild tissue in the joint. Fundamentally, the causes of OA development remain unknown. This talk will cover a potential underlying disease mechanism, “cellular senescence” and develop therapeutics to specifically target these cells in OA disease

Content

Senescent cells (SnCs) are a newly implicated factor in the development of OA that occur in associate with aging and trauma. “Cellular senescence” is characterized by a proliferation arrest, which protects against cancer, as well as other changes that can also contribute to aging phenotypes and pathologies¹. SnCs accumulate with age in many vertebrate tissues, including articular cartilage, where they promote pathological age-related deterioration. These and other tissue pathologies are presumably mediated by the secretion of extracellular proteases, proinflammatory cytokines, chemokines, and growth factors, termed the “senescence-associated secretory phenotype” (“SASP”), by SnCs. For years, the presence of SnCs in cartilage isolated from patients undergoing total knee artificial implants has been noted, but these cells’ relevance to disease was unclear. These cells, along with their inflammatory cytokine secretions, are responsible for OA development^{2, 3}. Thus, this presentation will focus on the causative role of SnCs in the development of posttraumatic and age-related arthritis along with a potential senolytic therapies that selectively remove SnCs as a new treatment for OA. The second part of this presentation will focus on SnCs-associated extracellular vesicles (EVs) and their contents such as microRNAs and proteins as a diagnostic for arthritic disease and indicator for therapeutic efficacy of senolytic treatment⁴.

References

1. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005 Feb.120(4):513–522.
2. Jeon OH, Kim C, Laberge R-M, Demaria M, Rathod S, Vasserot A, Chung JW, Kim DH, Poon Y, David N, Baker DJ, Deursen JM, Campisi J, and Elisseeff JH. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature Medicine. 2017 April. 23(6):775-781.
3. Jeon OH, David N, Campisi J, and Elisseeff JH. Senescent cells and osteoarthritis: a painful connection. JCI. 2018 April. 128(4):1229-1237.
4. Jeon OH, Wilson DR, Clement CC, Rathod S, Cherry C, Powell B, Lee Z, Khalil AM, Campisi J, Santambrogio L, Green JJ, Witwer KW, Elisseeff J. H. Senescence-associated extracellular vesicle serve as osteoarthritis disease and therapeutic markers. JCI Insight. 2019 April. 4(7):e125019.

Acknowledgments

The authors acknowledge financial support from a fellowship from the Glenn Foundation for Medical Research (to O.H. Jeon).