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Access Type

WSU Access

Date of Award

1-1-2010

Degree Type

Thesis

Degree Name

M.S.

Department

Biomedical Engineering

First Advisor

Weiping Ren

Abstract

Total hip replacement (THR) is a very well established surgery developed in the early 1960's. Implant loosening often occurs after the surgery causing the implant to fail. Successful osseointegration requires recruitment of bone marrow mesenchymal stromal cells (BMMSCs) to the periprosthetic site. Osteoblastic differentiation by BMMSCs is controlled by systemic and local growth factors. Bone morphogenetic proteins (BMPs) are a group of growth factors known to affect the formation of bone and cartilage, especially BMP2. Bisphosphonate and dexamethasone is also known to increase the proliferation and differentiation of BMMSCs. The purpose of this study was to find relations between the patient demographics and patient microenvironments. Also osteogenesis potential of BMMSC in response to BMP2, bisphosphonate, and dexamethasone were examined. A total of 12 patients were recruited and their bone marrow mesenchymal stromal cells (BMMSCs) were collected during the surgery. The cells were tested for density of BMP receptors by flow cytometry and gene profile by real time RT-PCR. Also alkaline phosphatase (ALP) activity was measured. Following the preliminary study, five patients were selected for osteogenesis study. The isolated BMMSCs were treated with BMP-2, bisphosphonate, and Dexamethasone in differential medium. Flow cytometry was used to measure intracellular signaling pSmad1/5 and BMP receptors BMPR-IA and BMPR-II. Alkaline phosphatase (ALP) activity was measured with cells cultured for 14 days.

The patient demographics showed no correlation with patient gene profiles. However, there were strong association between the % of Stro1+ cells and the genes expressing BMPR1A, MSX2, Runx2, and ALP. Also interestingly, we discovered a strong positive correlation between SOST (an inhibitor of BMP-induced osteoblast differentiation) expression and genes for BMPR-IA, ALP, and MSX2. The BMP induces various biological functions through signal transduction via BMP receptors. Our study was able to demonstrate the most induction of pSmad1/5 when treated with BMP-2 compared to the other treatments. BMMSCs expressed a highly diverse response to well-known osteogenic stimulators BMP-2, bisphosphonate, and dexamethasone. These findings, with a limitation of small sample size, suggest that more work is needed to elucidate whether the bone marrow osteogenic potential can be used to predict the long term outcomes of THR patients.