# Novel Molecular and Cellular Mechanisms for Osteoanabolic Action of Parathyroid Hormone

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $385,630

## Abstract

Project Summary/Abstract
Osteoporosis afflicts the elderly population and results from a disruption of the balance between osteoblastic
bone formation and osteoclastic bone resorption. Intermittent parathyroid hormone (PTH) by daily injection
increases bone formation, whereas continuous PTH causes bone resorption. However, the mechanisms by
which intermittent administration of PTH increases bone mass remain poorly understood; delineation of these
mechanisms could enable a refinement of PTH-based osteoporosis treatment. The anabolic PTH effects on
bone are mediated mostly by the Gs/cAMP signaling cascades and the canonical beta-catenin pathway that is
independent of Wnt, whereas Gq/PLC activation may antagonize these osteoanabolic actions. In addition, other
signaling pathways including PTH-stimulated PLD activity, ERK1/2 activation and PI3K/Akt signaling also affect
the anabolic PTH actions in bone. We have obtained considerable data suggesting the interaction of PTHR with
beta-catenin significantly constrains the anabolic effect of PTHR signaling, and disruption of this interaction with
a cell-permeable peptide constitutes a viable therapeutic approach for improving the efficacy of PTH in vivo. The
major goal of this proposal is to delineate the multiple elements of PTHR signaling that promote/restrain the
anabolic effects of PTH on bone. We will test the hypothesis that PTHR dissociates from beta-catenin and
subsequent trafficking of each induces distinct signaling pathways that mediate the anabolic action of PTH in
bone, and that a disruptor peptide that promotes PTHR-beta-catenin dissociation has pro-anabolic therapeutic
utility in vivo. Three aims are proposed to test this hypothesis. In aim 1, we will elucidate mechanisms whereby
beta-catenin coupling to PTHR elicits initial biased signaling of the PTHR, and the role of PTHR trafficking and
beta-catenin translocation in sustaining anabolic PTH signaling. Aim 2 will define the role of the disruptor peptide
in regulating multiple PTHR signaling pathways. In aim 3, we will directly assess whether disruption of beta-
catenin with PTHR increases osteoblast bone formation and reduces osteoclast bone resorption in vitro and in
vivo. Successful completion of the proposed research will contribute to a better understanding of the molecular
and cellular mechanisms mediating the actions of PTH on bone and advance a novel therapeutic modality to
improve PTH-based treatment for osteoporosis.

## Key facts

- **NIH application ID:** 9904602
- **Project number:** 5R01DK119280-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Bin Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,630
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904602

## Citation

> US National Institutes of Health, RePORTER application 9904602, Novel Molecular and Cellular Mechanisms for Osteoanabolic Action of Parathyroid Hormone (5R01DK119280-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9904602. Licensed CC0.

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