All ETDs from UAB

Advisory Committee Chair

Xu Cao

Advisory Committee Members

Xu Feng

Stuart J Frank

Christopher A Klug

Joanne Murphy-Ullrich

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) School of Medicine

Abstract

Bone remodeling depends on the precise coordination of bone resorption by the osteoclasts and bone formation by the osteoblasts. It is proposed that osteoclastic bone resorption releases factors to initiate bone formation, thereby, coupling the bone resorption and formation. Mesenchymal stem cells (MSCs) are progenitors of osteoblasts. Recruitment of MSCs in response to osteoclastic bone resorption may be an initial step for bone formation during bone remodeling process. Therefore, we have established an in vitro osteoclastic bone resorption system. Bone resorption condition medium have been tested to identify the factor inducing the migration of human bone marrow mesechymal stem cells (hBMMSCs). TGFβ1, in the bone resorption condition medium has been shown to be a primary factor inducing the migration of hBMMSCs. Indeed, osteoclastic bone resorption releases and activates TGFβ1 from the bone matrix. TGFβ-Smads signaling mediates, whereas, TGFβ-RhoA signaling confines the migration of hBMMSCs induced by the bone resorption condition medium. These data suggest that TGFβ1 may couple the bone resorption and the migration of MSCs during bone remodeling. To determine the role of TGFβ1 in recruiting MSCs in vivo, we have detected the MSCs on bone remodeling sites in TGFβ1 null mice. Depletion of TGFβ1 reduces MSCs counts on bone remodeling sites. Alternatively, data from tracing the BrdU-labeled hBMMSCs, which have been transplanted into mouse bone marrow cavity, indicate that deletion of TGFβ1 inhibits the recruitment of these labeled MSCs to the bone remodeling sites. Similarly, block of TGFβ signaling with a TGFβ1 receptor type I kinase inhibitor also reduces the recruitment of MSCs. Correlated with these observations, knockout of TGFβ1 causes a significant bone loss. These data suggest that TGFβ1 may couple bone resorption and formation through recruiting MSCs to the bone remodeling sites. Bone metastasis is a bone remodeling related disease. TGFβ1 released by bone resorption increases the formation of bone lesions in breast cancer patients. Since TGFβ1 is also a critic regulatory factor in bone remodeling, general inhibition of TGFβ signaling may lead to bone defect. Therefore, specific block of TGFβ signaling in breast cancer cells should be a better therapeutic choice. We found that expression of Smad7 in breast cancer cells significantly increases cell-cell adhesion and inhibits the invasiveness of cancer cells. Therefore, these findings may also provide a potential therapy for inhibiting bone metastasis.

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