Date of Award

7-2011

Embargo Period

10-11-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Advisor(s)

Phil G. Campbell

Second Advisor

Alan Waggoner

Third Advisor

Jonathan Jarvik

Fourth Advisor

Lee Weiss

Abstract

Management of bone reconstruction in the presence of inflammation is a challenging and costly clinical problem. It can result in extended repair times, poor bone healing, delayed unions, non-unions, revision surgery, and in the extreme, amputation or death. Acute inflammation can impair clinical reconstruction outcomes by compromising the early stages of bone repair and regeneration, while chronic inflammation exacerbates these effects leading to further significant loss of bone and associated function. Inflammation usually involves cells of the innate immune response, including neutrophils, macrophages and dendritic cells. Using J774a.1 (a mouse macrophage cell line) and fetal skin dendritic cells, I determined that lipopolysaccharide (LPS) induced a pro-inflammatory phenotype, which creates a microenvironment that inhibits bone morphogenetic protein 2 (BMP-2) induced stem cell osteoblastogenesis. However, the addition of an anti-inflammatory/immunoregulatory cytokine Interleukin 10 (IL-10), in the presence of LPS, directs this classical inflammatory response toward an alternative activated microenvironment that is permissive for BMP-2 osteoblastic differentiation. As BMP-2 can direct both osteoclastogenesis and osteoblastogenesis, the preference toward bone resorption or formation/repair thus appears to be influenced by the inflammatory microenvironment. When BMP-2 is in a predominately classic inflammatory microenvironment, it tends to promote osteoclastogenesis and when in an alternatively activated microenvironment, BMP-2 induces ostetoblastogenesis. Thus, controlling the microenvironment with IL-10 and/or similar immunoregulatory cytokines may determine the speed and success of BMP-2 mediated bone regeneration, especially under classic inflammatory conditions associated with situations such as infection and multi-tissue trauma.

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