Date of Award

5-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioengineering

Committee Chair/Advisor

Yongren Wu, PhD

Committee Member

Jeremy Mercuri, PhD

Committee Member

Tong Ye, PhD

Committee Member

Brian Burnikel, MD

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease in the world with an economic burden of nearly $140 billion annually. Factors identified to increase the risk of developing OA include age, obesity, sex, race, genetics, and previous joint injury. However, one risk factor that has been scarcely studied in OA etiology is cigarette smoking. While some studies have reported smoking to protect against OA, increasing evidence suggests that cigarette smoking results in more severe and painful OA, increases the rate of developing OA, and reduces the efficacy of pain medications and arthritis-targeting therapies. Despite this, the impact of cigarette smoking on OA disease progression remains controversial. This may be due to the lack of complexity utilized in current in vitro approaches, where culture models investigating the effects of cigarette smoking on OA do not adequately incorporate the cell and extracellular matrix (ECM) heterogeneity found in primary joint tissues.

To solve this problem, we employed a novel in vitro system using a combination of cartilage and synovium tissue explants with cigarette smoke extract (CSE) and OA-inducing inflammatory mediators, interleukin (IL)-1b and tumor necrosis factor (TNF)-a. With this model, we have for the first time, provided evidence on the negative effects that cigarette smoking has on OA-like characteristics in both cartilage and synovium at the cellular and tissue levels, as well as its effects on the communication and crosstalk between the two.

We found that under OA-like inflammation, CSE significantly increases the production of reactive oxygen species (ROS), alters the inflammatory secretory profile of the synovium, and magnifies the loss of ECM components in cartilage. Moreover, this model allowed for us to elucidate the involvement of cigarette smoke-induced advanced glycation end product (AGE) formation and the interaction with of AGEs with their receptor (RAGE). Our results suggest that CSE contains elevated levels of AGEs and their precursors, leading to accelerated AGE accumulation in cartilage with increased insoluble collagen and ROS production, both of which were able prevented by the addition of a potent AGE inhibitor, pyridoxamine (PM).

Altogether, we have shown that cigarette smoking can accelerate OA progression by altering synovial inflammation and increasing cartilage damage through the accumulation of AGEs and RAGE activation. By improving the breadth of knowledge regarding cigarette smoking and OA, this research may aid in the development of more effective pain relieving and/or disease modifying treatment options for OA patients who smoke.

Author ORCID Identifier

0000-0002-2072-6840

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