Molecular Mechanisms of Autologus Bone-Marrow Mesenchymal Stem Cells Alleviation of Allograft Bone-Mediated Excess Bone Resorption and Fibrosis in Segmental Defect of Rat Femur

Allograft bone transplantation is commonly used in reconstruction of the skeletal defect after tumor resection, multiple revision total joint arthroplsty and trauma. The use of massive allograft reconstruction has the advantages of no donor site morbidities, no limitation of size and length and possible healing to host tendon. However, in the clinical proactice, the complications related to allograft bone resorption after transplantation including nonunion, delayed union, allograft fracture and infection have been reported. Intense bone resorption and fibrosis in the conjunction between grafted bone and recipient bone are prominent pathologic reactions. However, the molecular mechanisms by which allograft bone induces excess bone resorption is not well defined. Bone-marrow mesenchymal stem cells (MSC) are multipotential to propagate toward osteogenic, chondrogenic and muscle cell lineages under well-controlled conditions, which are found to be important progenitor cell sources for regenerative medicine. In addition to tissue regeneration, MSCs are found to control osteoclastogenesis-regulator factors (osteoprotegerin, OPG and receptor activator NFkB ligand, RANKL) and inflammation and subsequently attenuate excess bone turnover and transplantation-mediated inflammation. Our preliminary data showed that conjunction between allograft bone and receipent bone displayed intense osteoclast recuritment and fibrous tissue formation. Autologous bone-marrow MSC therapy attenuated osteoclast number associated with decreased inflammatory cytokine IL-6 and osteoclast-promoting factor RANKL expression. Thus we hypothesize that MSCs may be through TGF-β1 signaling control the inflammation and resorption activity of microenvironment in the conjuction between allograft bone and receipent bone, which modulate OPG/RANKL and IL-6 expression and subsequently inhibits osteoclast differentiation then promotes bone regeneration of the defect. To test these hypotheses, we plant to conduct a three year reseach project as follow: The 1st year project: We intend to employ GFP-trangenic rat and extend sample size to elucidate the temporal changes of circulating and local osteoclast precursors and inflammatory cytokine expression in receipent. We also investigate whether MSC therapy could attenuate osteoclast recruitment and osteoclast-regulatory factor expression.

Project ID:PC10001-0098
External Project ID:NSC98-2314-B182A-104-MY3