# Targeting the ubiquitin-proteasome pathway to reverse catabolic action of PTH in bone

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $327,027

## Abstract

Project Summary/Abstract
 Intermittent parathyroid hormone (PTH) by daily injection increases bone formation, whereas continuous
PTH causes bone resorption and limits its therapeutic value. Understanding the molecular mechanisms that
promote both the beneficial anabolic PTH actions and the problematic adverse effects is critical to improving the
therapeutic efficacy of PTH-based treatments. The ubiquitin-proteasome pathway plays an important role in
regulating and controlling bone metabolism. The type 1 PTH receptor (PTHR) desensitizes in response to brief
exposure to PTH and sustained treatment with PTH downregulates the PTHR in osteoblasts. It is unknown
whether continuous PTH-caused bone loss is mediated through the ubiquitin-proteasome pathway. In studies
supported by an NIAMS R03 grant, we determined that continuous PTH treatment induces PTHR ubiquitination
and degradation, thereby inhibiting osteoblast differentiation and promoting osteoclast resorptive activity. In
addition, PTH activates multiple signaling pathways but not all of them are anabolic. Recent data from others
and our group have demonstrated that beta-catenin interacts with the PTHR carboxyl-terminal region and
switches PTHR signaling from Gs/cAMP to Gq/PLC activation. Furthermore, our preliminary data show that
ixazomib, a newly approved oral proteasome inhibitor with less toxicity, is able to block continuous PTH-induced
PTHR proteasomal degradation and reverse PTHR signaling switch by dissociating beta-catenin from the PTHR.
Based on these findings, we hypothesize that ixazomib is capable of converting the catabolic effect of continuous
PTH to an anabolic effect by blocking PTHR degradation and dissociating beta-catenin. The goals of our
proposed studies are to: 1) establish the proof-of-principle that inhibition of PTHR downregulation and PTHR
interaction with beta-catenin renders continuous PTHR activation more effective in promoting bone formation;
and 2) generate important pre-clinical data assessing the efficacy, safety, and side effects of ixazomib in our
murine model of continuous PTH-mediated bone loss. Three specific aims are developed to test this hypothesis
and achieve these goals, employing independent and complementary strategies. Aim 1 will detail how ixazomib
rescues continuous PTH-induced PTHR catabolic signaling. In Aim 2, we will establish whether ixazomib
converts continuous PTH catabolic effect to bone anabolism in vivo. Aim 3 will characterize mechanisms by
which ixazomib reverses the osteocatabolic effect of continuous PTH in vitro. Successful completion of the
proposed research will greatly advance our understanding of the mechanisms that promote/limit PTH effects on
bone formation, and provide strong basic and preclinical data that will clarify the path to a more effective
osteoporosis treatment.

## Key facts

- **NIH application ID:** 10130712
- **Project number:** 1R01AG071025-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Bin Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $327,027
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130712

## Citation

> US National Institutes of Health, RePORTER application 10130712, Targeting the ubiquitin-proteasome pathway to reverse catabolic action of PTH in bone (1R01AG071025-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10130712. Licensed CC0.

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