# MALIGNANCY-ASSOCIATED PTH-LIKE PEPTIDE--EFFECT ON BONE

> **NIH NIH R01** · YALE UNIVERSITY · 1989 · $131,464

## Abstract

Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome
which remains a serious therapeutic problem.  Its pathogenesis is poorly
understood.  Identification of the responsible mediator or mediators in this
syndrome had been an area of considerable investigative interest.  We have
recently purified and sequenced a peptide from two human and two animal
tumors which shows intense N terminal sequence similarity with parathyroid
hormone but differs in the rest of its primary structure (hACSP).  Full
length cDNA clones for this molecule have been identified and synthetic 1-36
and 1-74 fragments of the full length molecule synthesized.

We have shown that synthetic 1-36 hACSP and 1-74 hACSP are potent
bone-resorbing agents in vivo and in vitro. We have also isolated a similar
factor from normal human keratinocytes and identified mRNA species for this
molecule in several normal tissues. Taken together, these data suggest that
this peptide is a candidate for the mediator of HHM and is secreted by
non-malignant cells as well.

In studying the effects of this molecule on bone, we have demonstrated that
osteoblast-like cells when treated with hACSP release bone-resorbing
activity.  We have partially purified this bone-resorbing activity and
shown that it has a molecular weight of less than 6500 kd and is not due to
prostaglandin E2.  We have also demonstrated that these osteoblast-like
cells secrete a T cell growth factor in response to hACSP which has
biochemical and immunological properties consistent with those of
granulocyte macrophage colony-stimulating factor.

The goals of the current proposal are to:  1) Further characterize the
nature of the bone-resorbing activity released by clonal and primary
osteoblast-like bone cell cultures in response to hACSP.  2) To study the
nature and spectrum of released cytokines by osteoblasts in culture in
response to hACSP.  In these studies we plan to use both less specific
functional assays such as rat marrow culture systems as well as
cytokine-specific assays such as the HT2 assay.  3) Analyze the effects of
these peptides on osteoblast replication and differentiated osteoblast
function such as collagen production, osteocalcin release, and alkaline
phosphatase activity.

We expect that these studies will help illuminate the pathogenesis of the
syndrome of humoral hypercalcemia of malignancy and may begin to define a
physiologic role for this newly identified hormone.

## Key facts

- **NIH application ID:** 3159703
- **Project number:** 1R01AR039571-01A1
- **Recipient organization:** YALE UNIVERSITY
- **SAM.gov UEI:** FL6GV84CKN57
- **Principal Investigator:** KARL Leonard INSOGNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $131,464
- **Award type:** 1
- **Project period:** 1989-08-01 → 1992-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3159703

## Citation

> US National Institutes of Health, RePORTER application 3159703, MALIGNANCY-ASSOCIATED PTH-LIKE PEPTIDE--EFFECT ON BONE (1R01AR039571-01A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3159703. Licensed CC0.

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