# Biasing OGR1 signaling to optimizing PTH therapeutic effect

> **NIH NIH R21** · THOMAS JEFFERSON UNIVERSITY · 2020 · $205,920

## Abstract

Project Summary/Abstract
 Osteoporosis is a common metabolic bone disease and results from a disruption of the balance between
osteoblastic bone formation and osteoclastic bone resorption. Intermittent administration of PTH increases bone
mass, whereas continuous infusion of PTH promotes bone resorption. However, the mechanisms underlying the
distinct signaling pathways that generate this skeletal response remain poorly understood. It is well accepted
that acidosis suppresses osteoblastic bone formation and augments osteoclastic bone resorption. Ovarian
cancer G protein-coupled receptor 1 (OGR1), a member of the proton sensing GPCR family, transduces
extracellular pH signals primarily into Gq/PLC signaling in bone. Both published studies and our preliminary data
have demonstrated PTH receptor and OGR1 promote a concomitant activation of anabolic Gαs/cAMP and
catabolic Gαq/PLC signaling pathways. It has been observed that some benzodiazepines such as lorazepam
cause bone fractures. We have demonstrated that lorazepam acts as a Gq-biased allosteric modulator of OGR1
to preferentially induce Gq/PLC signaling. These findings suggest that the association between lorazepam use
and bone fracture may be ascribed to OGR1 biased signaling. Our preliminary data show that continuous PTH
treatment promotes lactic acid production and increases OGR1 expression, and that sulazepam (another
benzodiazepine) acts as an allosteric modulator of OGR1 to bias OGR1 signaling toward the Gαs/cAMP
(therapeutic) pathway. Based on these findings, we hypothesize that OGR1 mediates the catabolic effect of
continuous PTH on bone, and sulazepam can bias OGR1 signaling to “tune” PTH receptor signaling toward its
therapeutic pathway. Two specific aims are proposed to test this hypothesis. Aim 1 will establish whether
sulazepam converts continuous PTH catabolic effect to bone anabolism in vivo. In Aim 2, we will characterize
the mechanisms by which sulazepam reverses the catabolic effect of PTH by promoting biased OGR1 signaling
in vitro. We predict that sulazepam but not lorazepam shifts the catabolism of continuous PTH toward an anabolic
effect on bone by promoting Gs-biased OGR1 signaling. Successful completion of the proposed studies will not
only advance our understanding complex effects of PTH on bone, but also provide evidence that targeting Gs-
biased OGR1 signaling can shift continuous PTH treatment toward to therapeutic effect.

## Key facts

- **NIH application ID:** 9896526
- **Project number:** 1R21AR075293-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Bin Wang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $205,920
- **Award type:** 1
- **Project period:** 2020-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896526

## Citation

> US National Institutes of Health, RePORTER application 9896526, Biasing OGR1 signaling to optimizing PTH therapeutic effect (1R21AR075293-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9896526. Licensed CC0.

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