# PROJECT 4 - Kyn-AhR crosstalk with nuclear receptor-mediated signaling in skeletal aging

> **NIH NIH P01** · AUGUSTA UNIVERSITY · 2023 · $296,758

## Abstract

Project Summary/Abstract: Our group has demonstrated that increasing levels of the oxidized tryptophan
metabolite kynurenine (Kyn), and downstream signaling through its activation of the aryl hydrocarbon receptor
(AhR), contribute to age-related musculoskeletal dysfunction. Surprisingly, however, Kyn exerts more
deleterious effects on the female musculoskeletal system as compared to its effects in males. The molecular
mechanism behind this dimorphic phenomenon is not yet known, but our results suggest strong relevance to the
pathophysiologies of osteoporosis and frailty, which are more prevalent in women than in men. Our working
hypothesis is that the sexually dimorphic effects of Kyn in the musculoskeletal system may be attributed to
crosstalk between Kyn/AhR and signaling downstream of ligand-regulated DNA-binding transcription factors in
the nuclear receptor superfamily including the estrogen receptor (ER alpha/beta) and the glucocorticoid receptor
(GR). Glucocorticoids (GC) are key mediators of stress responses that regulate skeletal homeostasis. During
aging, endogenous GC levels increase, lose proper circadian regulation, and show amplified local activation
from increased expression of GC-activating enzymes (e.g., Hsd11b1) with age in bone. Despite the known
inhibitory effects of exogenous GC in bone, our data suggest that endogenous GC/GR-mediated signaling in
osteoblasts is protective for aging bone, as loss of GR signaling in osteoblasts promoted low bone mass and
increased bone marrow adipose tissue (BMAT). As we saw with Kyn, these effects from impaired GC/GR
signaling in bone are more severe in female than in male mice, and preliminary data suggest that the deleterious
effects of Kyn on osteoblasts are linked to impaired GC signaling. Therefore, the objective of Project 4 is to
understand AhR function with age, and determine the molecular mechanisms by which Kyn, and crosstalk
between Kyn/AhR and the nuclear receptors described above, drives aging-related phenotypes in bone and its
resident cell populations, with the ultimate goal of identifying novel targets to mitigate these effects

## Key facts

- **NIH application ID:** 10691511
- **Project number:** 5P01AG036675-12
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Meghan E. McGee-Lawrence
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $296,758
- **Award type:** 5
- **Project period:** 2011-05-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691511

## Citation

> US National Institutes of Health, RePORTER application 10691511, PROJECT 4 - Kyn-AhR crosstalk with nuclear receptor-mediated signaling in skeletal aging (5P01AG036675-12). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10691511. Licensed CC0.

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