# Role of Desumoylase SENP6 in Joint Aging and Osteoarthritis Development

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2021 · $498,490

## Abstract

PROJECT SUMMARY
For decades, it has been known that the inflammatory and catabolic environment in the joints accelerates oste-
oarthritis (OA) development. However, current OA therapies that inhibit this environment are not curative, as
they do not target the underlying cause of such an environment. It was recently shown that senescent articular
chondrocytes (ACs) are a major source of inflammatory and catabolic factors. Last year, it was reported that
eliminating senescent ACs can alleviate the progression of age-related and post-traumatic OA in mice. While
this suggests a potential treatment avenue, ideally, we would also identify the root causes (i.e. the pathways)
that lead to AC senescence, and target those to prevent or slow the transition to senescence in the first place.
Our long-term goal is to examine the mechanisms that lead to AC senescence, so that strategies can be devel-
oped for prevention and/or treatment of OA. To that end, data from a genome-wide association study (arcO-
GEN Consortium, 2012) showed a strong association of OA with SENP6, which is an enzyme (desumoylase)
that reverses SUMO modifications on specific protein targets. We found this intriguing, because sumoylation is
an enzymatic pathway that has been associated with both the stress response and the aging process, and is
potentially druggable. My lab has reported the correlations among the SENP6 pathway, cell senescence, and
stress response in skeletal progenitors. Also, we showed that this occurs partially via over-sumoylation of
TRIM28, an epigenetic regulator associated with senescence. Moreover, our preliminary work found that
SENP6 loss in cartilage accelerated AC senescence and OA in mice, providing a rationale for further examin-
ing the role of SENP6. The hypothesis is that SENP6 reduces OA susceptibility by suppressing AC senes-
cence induced by stress response and epigenetic alterations. To test this hypothesis, our first goal is to deter-
mine the future viability of SENP6 as a possible target for treatment; we will examine the extent to which gain
of SENP6 function reduces OA progression. Next, because our preliminary work suggested an interplay be-
tween SENP6 stability and stress response, the second goal is to determine how stress induces SENP6 degra-
dation and how the underlying mechanism affects AC senescence. Our third goal is to identify SENP6-orches-
trated epigenetic alterations and their role in AC senescence. This is inspired by the facts that epigenetic alter-
ations are a hallmark of aging and that our and other's findings suggest a potential role for the SENP6–TRIM28
axis in the epigenetic regulation of gene expression and inflammation. It is expected that this proposed work
will have a broad impact by uncovering a new mechanism that connects the sumoylation pathways to stress
response, epigenetic alterations, senescence, joint aging, and OA. These results will form a basis for develop-
ing new OA treatments by inhibiting AC senescence thr...

## Key facts

- **NIH application ID:** 10165450
- **Project number:** 5R01AG061086-03
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Tao Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $498,490
- **Award type:** 5
- **Project period:** 2019-07-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165450

## Citation

> US National Institutes of Health, RePORTER application 10165450, Role of Desumoylase SENP6 in Joint Aging and Osteoarthritis Development (5R01AG061086-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10165450. Licensed CC0.

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