# COX-2 Functions in Bone Fracture Healing

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $425,440

## Abstract

ABSTRACT
Our goal is to manipulate the molecular pathways controlling fracture healing in order to increase the
proportion of fractures that successfully heal and to reduce healing and recuperation times. Despite advances
in methods to reduce and stabilize bone fractures, delayed and impaired healing still occurs in 5-10% of all
bone fractures. In addition, significant mortality occurs in older patients that have suffered hip or other severe
fractures. Often mortality is associated with secondary complications caused by immobility during recuperation,
such as pneumonia. Thus there is a significant clinical need for methods to improve fracture healing outcomes
and reduce recuperation times. Mouse genetics has identified several genes and pathways that regulate bone
regeneration. Our laboratory has focused on understanding the role of lipid mediators in controlling fracture
healing. Lipid mediators such as prostaglandins are synthesized by cyclooxygenase activity (COX-1 or COX-2)
and are well-known for promoting inflammation. We found that inhibiting COX-2 significantly impairs fracture
healing in rodents and similar effects have been noted in humans. As inflammation is one of the first
physiological responses to fracture, it was assumed that inhibition of COX-2 impaired inflammation leading to
impaired fracture healing. Recent data indicate otherwise as COX-2 expression during fracture healing peaks
after the inflammatory phase and COX-2 expression in the fracture callus occurs in proliferating chondrocytes
and osteoclasts. We theorize that callus osteoclasts provide similar functions as macrophages do during
wound healing. Polarity switching between inflammatory and regenerative macrophages is well established
during wound healing. As osteoclasts derive from the same cellular progenitors as macrophages, perhaps
osteoclasts also have multiple polarities such as resorbtive and regenerative osteoclasts. Our preliminary data
supports this concept in that depletion of monocyte-derived cells delays fracture healing rather than increases
callus bone volume. In addition, we show that deletion of COX-2 from monocyte-derived cells also impairs
fracture healing, indicating a specific role for COX-2. Here we further explore the regenerative osteoclast
concept and the function of COX-2 in fracture healing by determining whether COX-2 activity in osteoclasts is
required for normal fracture healing (Aim 1), how COX-2 expression is controlled in osteoclasts (Aim 2), and
whether integrin receptors or integrin ligands are necessary for osteoclast COX-2 expression during fracture
healing (Aim 3). Successful completion of these experiments will demonstrate a COX-2-dependent regulatory
role for osteoclasts in controlling fracture healing.

## Key facts

- **NIH application ID:** 10008970
- **Project number:** 5R01AR069044-05
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** J Patrick O'Connor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,440
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10008970

## Citation

> US National Institutes of Health, RePORTER application 10008970, COX-2 Functions in Bone Fracture Healing (5R01AR069044-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10008970. Licensed CC0.

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