Project Summary/Abstract
Most older adults (~70 years of age) have some signs of osteoarthritis (OA) in their joints. Development of OA
can also be accelerated by ~20 years in individuals who are obese. This phenomenon does not stem solely from
greater mechanical loading, obesity also increases OA risk in non-weight-bearing hand joints. Obesity can
produce adverse outcomes in part because it alters metabolism at both a whole-body level and a cellular level.
However, it is unknown how joint cells change metabolism during aging and obesity. Identifying metabolic
changes in joint cells during aging and obesity could inform effective interventions and therapeutic strategies
that reduce the incidence and impact of OA, especially in the context of an increasing prevalence of obesity and
extended lifespans. This project will investigate a new theory of cell metabolic damage called "carbon stress",
which describes how over-nutrition causes metabolic byproducts to accumulate in cells, bind to metabolic
proteins, and decrease protein activity. We hypothesize that obesity-associated ‘carbon stress’ also occurs in
cartilage (chondrocytes) and plays an important role in OA development. Our previous work shows that one type
of carbon stress associated with protein post-translational malonylation (MaK) is highly elevated in cartilage
during obesity. We also showed that Sirt5, an enzyme that can remove MaK, declines during aging, suggesting
that cellular defenses against carbon stress are compromised during aging. Yet how do MaK and its regulatory
pathways contribute to cellular metabolism in chondrocytes? Guided by our preliminary data and the literature,
we will investigate this question via two specific aims: Aim 1. To test the hypothesis that obesity promotes MaK
to accelerate OA development; Aim 2. To determine the mechanisms by which Sirt5-MaK regulates cartilage
degeneration under obesity associated pro-inflammatory condition. Well-established mouse models of diet-
induced obesity and OA will be used in combination with genetically modified mouse models that allow
conditional deletion of MaK regulatory genes in cartilage. Mouse OA phenotyping will be used to examine the
consequences of enhancing or inhibiting MaK on OA pathology. In vivo and in vitro metabolic profiling methods
will be leveraged to determine the effects of manipulating MaK on chondrocyte cellular metabolism. Successful
completion of this research is expected to provide more comprehensive understanding of how obesity and aging
damage metabolism in joint cells and promote OA development, offering the potential to provide new therapeutic
targets for OA treatment. The proposed project will also serve as a perfect vehicle for the PI to continue the on-
going endeavor of mentoring students and engaging students in biomedical research.
