# Regulation of PTH-induced RankL transcription in osteoblasts

> **NIH NIH F31** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $46,036

## Abstract

Abstract: Osteoporosis is a prevalent disease of aging characterized by a decrease in the density and quality
of bone tissue and is associated with substantial morbidity/mortality. In osteoporosis the homeostatic processes
that form new and remove old/damaged bone are dysregulated, promoting excessive resorption. Parathyroid
hormone (PTH) is a key regulator of this homeostasis and along with its analogs has been used to treat
osteoporosis. Although PTH has positive anabolic effects on bone it can also stimulate catabolism through
activity of receptor activator of nuclear factor kappa-β ligand (RankL). Treatment of osteoporosis via PTH is
limited by a short “anabolic window,” after which the positive effects are mitigated by the resorption initiated by
RankL. Theoretically, it may be possible to retain just the positive effects of PTH-derived treatments if
transcription of RankL can be inhibited. PTH and its analogs bind the same receptor on osteoblasts, activating
a signaling cascade leading to RankL transcription. Recent work has implicated a cascade of messengers,
enzymes, kinases, and phosphatases in regulating the two coactivators of RankL transcription. The exact
mechanisms that cause this regulation and the transcription factor(s) the coactivators associate with to initiate
RankL transcription are not established. The purpose of this research is to identify the specific regulatory
mechanisms and transcription factor(s) that activate RankL transcription. In completing the aims and training
plan outlined in this proposal the graduate student, Michael Mosca, will gain substantial experience in new
biochemical techniques, will gain specific knowledge in endocrinology and pharmacology, and will expand his
expertise in musculoskeletal tissues to include bone. This research training will build on his biomechanical and
histological experiences related to inflammatory and fibrotic mechanisms of muscle, tendon/ligament pathologies
and will prepare him for a research career as an independent investigator in the musculoskeletal field.
 Aim 1.1 will determine the specific individual and/or combined regulatory roles that several salt-inducible
kinases and protein phosphatases have on cAMP-regulated transcriptional coactivators 2/3 (CRTC2/3). First, a
series of siRNA transfections will be performed with primary calvarial osteoblasts to explore the effects of
knocking down each factor on RankL transcription via qRT-PCR. Then, the effect the knockdowns have on
CRTC2/3 nuclear translocation will be determined with and without PTH-treatment via quantitative
immunofluorescence. Aim 1.2 will assess the roles CRTC2/3 play as RankL co-activators throughout osteoblast
differentiation using similar methods. Aim 2 seeks to identify the transcription factor(s) that CRTC2 and CRTC3
each associate with to activate RankL transcription using Mass Spectrometry, Chromatin-immunoprecipitation,
and siRNA knockdowns. RankL expression is responsible for catabolism seen in trea...

## Key facts

- **NIH application ID:** 10247514
- **Project number:** 5F31DK126539-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Michael Joseph Mosca
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247514

## Citation

> US National Institutes of Health, RePORTER application 10247514, Regulation of PTH-induced RankL transcription in osteoblasts (5F31DK126539-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247514. Licensed CC0.

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