Metal orthopedic implants are common devices used for restoring musculoskeletal joint function and patient mobility. Given the large number of orthopedic joint reconstructions conducted each year, it is important to minimize rates of aseptic implant loosening which causes pain and often leads to revision surgery. Therapeutics that modify endogenous epigenetic processes are promising for the treatment of many musculoskeletal disorders, including osteopenia and osteoporosis, yet the delivery mode and molecular mechanisms that act to diminish clinical symptoms are in need of further investigation. The central hypothesis of the proposed project is that osseointegration of orthopedic implants can be improved by modulating the biological properties of endogenous skeletal repair cells using epigenetic inhibitors. Based on recent preliminary data, this amended proposal has evolved to address the specific working model that epigenetic drugs can be used to stimulate paracrine signaling (e.g., BMP2 activity) to drive endogenous skeletal repair cells into the osteoblast lineage. New data I generated show that human mesenchymal stromal cells (both adipose and bone tissue-derived) attach to porous metal orthopedic implants, as well as proliferate and deposit an extracellular matrix. Additional preliminary data reveal that Ezh2 inhibition can bolster the differentiation of MC3T3 pre-osteoblasts, both in vitro and in vivo. Based on these preliminary data, this study will (i) determine the in vivo effects of Ezh2 delivery before, during or after reconstructive orthopedic surgery (Aim 1), and (ii) examine the mechanism of Ezh2 inhibition by measuring the effects of blocking paracrine signaling (e.g., BMP2) on osteoblast differentiation in vitro (Aim 2). My long term goals are to develop strategies for localized delivery of bone anabolic therapeutic reagents to address the increasing demands of an expanding, aging, and increasingly active human population. These studies should ultimately lead to the development of surgeon- assembled adjuvants and become part of routine orthopedic practices, as well as support my career progression as an independent investigator capable of executing clinically relevant translational research similar to that proposed here.

Public Health Relevance

Metal orthopedic implants are essential for restoring mobility to patients with serious joint problems. However, one important clinical problem arises when prosthetic devices do not fix permanently to native bone, and this aseptic loosening requires revision surgery. The goal of this proposal is to assess the potential of molecular and pharmacological strategies to promote new bone formation around the implant in animal models. The mouse experiments we propose will simulate treatments to promote the attachment of implants to bone that could be given to patients before, during or after their joint reconstruction surgery to increase the speed, efficiency, and durability of implant fixation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AR068154-01A1
Application #
9251354
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Washabaugh, Charles H
Project Start
2016-09-21
Project End
2018-06-20
Budget Start
2016-09-21
Budget End
2017-09-20
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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