Translation Study of Dickkopf-1 Signaling Modulation Strategy for Alleviation of Abnormal Bone Metabolism in Osteogenesis Imperfecta (Oi) Animals

Osteogenesis imperfecta (OI) is a rare inherited skeletal disorder characterized by skeletal deformity, low bone mass and biomechanical strength and delayed healing in fracture bone. Molecular pathomechanisms underlying OI are complicate. Mutations of gene coding type 1 collagen α1 and α2 chain reportedly correlates with mild and moderate types of OI. Emerging evidence demonstrates that mutation of gene coding regulatory factors responsible for collagen post-translational modification which induces loss of ultrastructure integrity and mechanical characteristic of collagen fibril are associated with severe and lethal types of OI. We have recently found that altered abundances of serum proteins correlated with decreased bone mineral density in mild and moderate types of OI (Bone 2010, in revision). In OI animal models, skeletal integrity loss of OI correlates with excess immature osteoblast differentiation and osteoclast activation. In clinical trials and experimental animal models, biphosphonates, growth hormone, inhibition of osteoclast-promoting factor RANKL or mesenchymal/hematopoietic stem cell graft reportedly alleviate bone mass loss in OI subjects. Therefore, we hypothesize that changing excess bone turnover in skeletal microenvironments potentially attenuates bone loss, thereby improving skeletal deterioration in OI. Dickkopf-1 (Dkk-1) is found to act as an endogenous inhibitor of Wnt/β-catenin signaling component and participate in skeletal tissue development and osteogenic differentiation in mesenchymal stem cells. In clinical vignettes, Dkk-1 expression reportedly correlates with incidence of osteoporosis, joint disorder and cancer cell-mediated bone metastases. We have found that increased Dkk-1 expression was correlated with chondral cell death in osteoarthritic joint cartilage (Osteoarthritis and Cartilage 2009;17:919-929) and osteoblastic cell apoptosis and severity of femoral head osteonecrosis (Bone 2010;46:584-591). Moreover, blockade of Dkk-1 attenuated bone loss and biomechanical property and protected joint cartilage integrity in ovariectiomized animals (Bone 2007;40:485-492), supraphysiological glucocorticoid-treated animals (Endocrinology 2008;149:1793-1801) and ACLT-induced rat knee osteoarthritis (Arthritis and Rheumatism 2010;62:1393-1402), indicating that inhibition of Dkk-1 action is beneficial for bone and joint homeostasis. Our preliminary data showed that compared with normal subjects, OI patients had increased serum Dkk-1 concentrations. Bone-marrow mesenchymal progenitor cells from OI patients underwent osteotomy displayed increased Dkk-1 expression but decreased collagen 1α1 expression and osteogenic differentiation. Knock down of Dkk-1 restored collagen 1α1 expression and bone formation activity. We further hypothesize that interruption of Dkk-1 expression is a potential strategy for improving bone formation and bone tissue integrity in OI. In order to test whether control of Dkk-1 can decrease bone mass loss in OI, we will extend sample size and use OI mice to perform following translational studies: (1) effect of changing Wnt/Dkk-1 signaling on osteogenic differentiation and collagen expression in mesenchymal progenitor cells harvested from OI patients; (2) effect of knocking down Dkk-1 on bone mass and skeletal microstructure in OI mice; (3) influence of knocking down on osteogenic cells/osteoclastogenic cell distribution and differentiation capacity and signaling transduction pathways in skeletal microenvironments of OI mice.

Project ID:PC10007-1172 
External Project ID:NSC100-2314-B182-007-MY3