Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis

Tae Hwan Gil, Haiyan Zheng, Hyo Gyeong Lee, Ji Won Shin, Sun Wook Hwang, Ki-Mo Jang, Ok Hee Jeon

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Aging is a risk factor for the development of osteoarthritis (OA), a progressive joint disease leading to cartilage damage, pain, and loss of function. In a mouse model of OA, senolytic drugs to selectively clear senescent cells (SnCs) that accumulate with injury or aging yielded a chondroprotective effect; however, this therapeutic benefit was limited in aged mice. Due to inconsistency between cartilage destruction and pain-associated symptoms, we studied the therapeutic effect of senolytics on joint pain in spontaneous OA. We orally treated 21 and 22-month old mice with an ABT263 and Dasatinib and Quercetin (D+Q) drug combination. Selective elimination of the SnCs that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. Selective removal of the SnCs from in vitro cultures of synovial cells from human OA patients also decreased expression of senescent markers, axonal growth-promoting factors, such as NGF, and angiogenesis markers. We suggest that systemic administration of ABT263 and D+Q is an exciting therapeutic approach to age-related OA pain.

Original languageEnglish
Pages (from-to)6006-6027
Number of pages22
JournalAging
Volume14
Issue number15
DOIs
Publication statusPublished - 2022

Bibliographical note

Funding Information:
This study was supported by the Korea University Grants K2119251 (O.H.J.) and the National Research Foundation of Korea 2020R1C1C1009921 (O.H.J.).

Publisher Copyright:
© 2022 Gil et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords

  • Nociceptive pathways
  • Pain
  • Senescence
  • Senolytics
  • Spontaneous osteoarthritis

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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