# SYNTHESIS OF OSTEOCALCIN IN BONE

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 1992 · $314,244

## Abstract

Osteocalcin (OC), a vitamin K dependent calcium binding protein, is the
only known bone-specific protein.  It is a significant component of the
extracellular matrix and circulating levels are widely used as a clinical
marker of bone turnover.  Osteocalcin synthesis and gene expression are
modulated by numerous physiologic factors that are known to regulate
osteoblast function, including steroid hormones.  We have developed a
normal diploid rat osteoblast culture system that produces a bone-like
extracellular matrix to study regulation of OC within the complexity of
changes that occur during extracellular matrix formation and
mineralization.  We have documented the differential expression and
selective modification of osteocalcin by steroid hormones during the
developmental sequence of osteoblast differentiation.  We have cloned the
rat OC gene, identified its vitamin D responsive element and a primary
transcriptional regulatory element, both of which contain AP-1 sites that
bind the oncogene encoded fos-jun proteins.  It is known for other genes
that transcription is regulated by interactions between independent
elements as well as by multiple classes of transcription factors within a
regulatory element.  The synergistic and antagonistic effects of steroids
on OC gene expression suggests that such regulatory mechanisms are
operative.  We propose to use normal diploid osteoblasts and a panel of
chimeric gene constructs with deletions or targeted mutations in promoter
regulatory elements to (1) define the levels and mechanisms at which
regulation of osteocalcin gene transcription is mediated, both in vitro and
in vivo (transgenic mice) in relation to tissue specificity bone
development; (2) define physiologic mediators (vitamin D, glucocorticoid,
estrogen) of OC gene transcription by characterizing the positive and
negative promoter regulatory sequences, their cognate sequence-specific
transcription factors, and the functional proximity of regulatory elements
from chromatin structure studies; and (3) carry out functional studies by
altering (by inhibition or premature upregulation) of OC expression.  A
systematic analysis of the OC promoter, focusing on positive and negative
regulatory elements and steroid responsive elements that regulate OC gene
transcription, we will make a contribution towards understanding its role
in bone metabolism and, in a broad biological context, elucidate mechanisms
associated with the regulation of genes by physiologic modulators.

## Key facts

- **NIH application ID:** 3156676
- **Project number:** 2R01AR033920-09
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **SAM.gov UEI:** MQE2JHHJW9Q8
- **Principal Investigator:** Jane B. Lian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $314,244
- **Award type:** 2
- **Project period:** 1989-04-01 → 1996-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3156676

## Citation

> US National Institutes of Health, RePORTER application 3156676, SYNTHESIS OF OSTEOCALCIN IN BONE (2R01AR033920-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3156676. Licensed CC0.

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