# Cox-2 Regulation of Bone Responses to PTH:  Role of Osteoclasts

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $347,223

## Abstract

Project Summary
Intermittently injected parathyroid hormone (PTH) is a key anabolic therapy for osteoporosis, stimulating bone
formation more than resorption. Paradoxically, continuously elevated PTH causes bone loss. We have
identified a factor that may explain the paradox. PTH is a potent inducer in osteoblastic lineage cells of both
cyclooxygenase 2 (Cox2), the major enzyme producing prostaglandin E2 (PGE2), and receptor activator of
nuclear factor κB ligand (RANKL), which is required to commit bone marrow macrophages (BMMs) to become
osteoclasts. RANKL and Cox2/PGE2 together cause BMMs to secrete a factor that suppresses the ability of
continuous PTH to stimulate differentiation of osteoblasts. Using in vitro cell models, we identified the inhibitory
factor as serum amyloid A3 (Saa3), an acute phase protein generally associated with inflammation or infection,
and showed that Saa3 inhibited PTH-stimulated osteoblast differentiation by blocking PTH-stimulated cAMP
production. As predicted by the in vitro models, PTH infusion in wild type (WT) mice suppressed bone
formation and caused bone loss, but PTH infusion in in Cox2 knockout (KO) mice was markedly anabolic for
bone. In contrast to the effects on formation, PTH infusion stimulated bone resorption equally in WT and Cox2
KO mice. We have generated a mouse with global KO of Saa3. We will test the hypothesis that Saa3
suppresses the anabolic, but not the catabolic, responses to continuously elevated PTH in vivo. Specific aim 1
will examine effects on bone formation and resorption of Saa3 in in vivo models for elevating PTH. Aim 2 will
examine the effect of Saa3 on PTH-stimulated osteoblast and osteoclast differentiation in vitro and the cAMP-
dependent actions by which PTH regulates Wnt signaling and the cAMP–independent signaling pathways by
which PTH regulates RANKL signaling in our models. Aim 3 will examine the requirement for PGE2 and its
EP4 receptor in the induction of Saa3 in BMMs and the role of Saa3 in stimulating other cytokines that can
regulate the bone environment. We are proposing a novel role for Saa3; a new means by which osteoclasts
regulate osteoblasts; and a novel role for Cox2/PGE2. The results of this study should strengthen our
understanding of the molecular mechanisms underlying actions of PTH and may help us target bone
remodeling more effectively to treat osteoporosis and other skeletal diseases.

## Key facts

- **NIH application ID:** 9949642
- **Project number:** 5R01AR060286-10
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** CAROL C. PILBEAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,223
- **Award type:** 5
- **Project period:** 2011-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949642

## Citation

> US National Institutes of Health, RePORTER application 9949642, Cox-2 Regulation of Bone Responses to PTH:  Role of Osteoclasts (5R01AR060286-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9949642. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*