# Nuclear Events in PTHR1 Action on Bone

> **NIH NIH R56** · NEW YORK UNIVERSITY · 2021 · $158,500

## Abstract

Parathyroid hormone (PTH) is an essential regulator of calcium homeostasis and became the prototypic
osteoanabolic hormone for treating osteoporosis. On the other hand, hyperparathyroidism, with its consequent
bone breakdown, is a major problem in and of itself and in chronic renal failure. The hormone acts through its
G-protein-coupled receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. To do this,
the osteoblast produces receptor activator of nuclear factor kappa-β ligand (RANKL) in response to PTH.
RANKL is widely considered a principal mediator of PTH-induced bone catabolism and has been associated
with bone loss in hyperparathyroidism. Our work in the last cycle of this grant revealed that PTH activates
cAMP/protein kinase A (PKA) to inhibit salt-inducible kinases (SIKs) and requires protein phosphatases (PPs) to
stimulate Rankl expression in osteoblasts. Knockdown of salt-inducible kinases (SIKs) 2 and 3 and cAMP-
regulated transcription coactivators 2 and 3 (CRTC2 and 3) indicated that all four are part of this pathway.
Moreover, inhibition of serine-threonine protein phosphatases decreased both PTH-induced Rankl expression
and the stimulation by PTH(1-34) of CRTC2 and 3 translocation into the nucleus. Upon entry into the nucleus,
these CRTCs associate with unknown basic leucine zipper domain (bZip) transcription factor(s), activating
Rankl transcription through binding to its distal PTH-responsive cAMP-response elements (CREs). From these
data of cells in culture and preliminary data in vivo, we have developed the central hypothesis that SIK/PP
regulation of CRTC2/3 is essential to their function in the skeleton, and PTH controls this regulation. The long-
term goals of this work are to delineate the signaling and transcriptional regulatory mechanisms conveying
PTH action in bone. Consequently, the specific aims to test our hypothesis of this competing renewal proposal
focus on the SIK and PP regulation of CRTC2/3 function and action on Rankl, and will, 1) determine the
mechanism of PTH regulation of Rankl transcription in osteoblasts by a. elucidating the regulatory mechanisms
involved in CRTC2/3 nuclear translocation in osteoblasts, b. identifying the bZIP transcription factor(s)
responsible for CRTC2/3-induced Rankl transcription, 2) determine the role of CRTC2/3 in bone development
and PTH's anabolic and catabolic effects by a. determining the site and role of osteoblast CRTC2/3 in bone
development, b. ascertaining the effects of deletion of CRTC2/3 on PTH's anabolic and catabolic actions in
bones of adult mice. The results of this work will make major contributions to our knowledge of how PTH exerts
its nuclear effects on skeletal function through the SIK/PP/CRTC/bZip pathway. In so doing, the data will also
provide new perspectives into treatment of disorders of calcium metabolism and other severe diseases
functioning through PTHR1.

## Key facts

- **NIH application ID:** 10337446
- **Project number:** 2R56DK047420-27
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Nicola C Partridge
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $158,500
- **Award type:** 2
- **Project period:** 1994-12-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337446

## Citation

> US National Institutes of Health, RePORTER application 10337446, Nuclear Events in PTHR1 Action on Bone (2R56DK047420-27). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10337446. Licensed CC0.

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