| Osteoporosis is a serious public health issue. The past 10 years have seen great advances in our understanding of its epidemiology, pathophysiology, and treatment, and further advances are rapidly being made. Clinical assessment will probably evolve from decisions mainly being made on the basis of bone densitometry, to use of algorithms of absolute fracture risk. Biochemical markers of bone turnover are also likely to become more widely used. Bisphosphonates will probably remain the mainstay of therapy, but improved understanding of the optimum amount of remodeling suppression and duration of therapy will be important. At the same time, other diagnostic and therapeutic approaches, including biological agents, are likely to become more widespread.Wnt signaling pathway plays a central role in many processes during embryonic development and in later stages of life. At least three distinct wnt signaling pathways have been described. In 2001, evidence was obtained from genetic studies on some rare hereditary conditions, that the canonical wnt signaling pathway plays an important role in bone formation. Functional studies and experimental analysis of relevant animal models confirmed the anabolic effect of wnt signaling by modulating the differentiation, the proliferation, the activity and finally the apoptosis of (pre)osteoblasts and osteocytes. More recently, also non-canonical wnt signaling was shown to play a role in bone formation. Since there is currently a major lack of anabolic therapeutic agents for the prevention and treatment of osteoporosis this signaling pathway deserves major attention. A big concern, however, is the pleiotropic function of the pathway that needs to be taken into account in order to avoid unwanted side-effects. Preliminary data are already indicating that this might be achieved by targeting sclerostin, a bone-specific extracellular antagonist of canonical wnt signaling.The development of bone-rebuilding anabolic agents for potential use in the treatment of bone-related conditions, such as osteoporosis, has been a long-standing goal. Recent advances in the field of skeletal development and osteogenesis have demonstrated that signaling through the Wnt pathway is critical for the differentiation of progenitor cell lines into osteoblasts. Genetic studies in humans and mice have shown that the DKK-1 protein is a key negative regulator of Wnt signaling pathway, which regulate bone formation process, and inhibition of such signals can predispose MSCs to cell cycle entry and inhibit osteogenesis. Here, we report that synthetic peptides derived from the second cysteine-rich domain of the canonical Wnt inhibitor Dickkopf-1 (DKK-1) have utility in controlling the differentiation of C2C12 and MC3T3-E1 cells, and alter estrogen loss-induced bone loss. To explore the effects of DKK-1 peptides inhibition in the differenetiation of pre-osteoblast, we used cell culture of C2C12 and MC3T3-E1 to test the ALP activity and mineralization extent. We found that peptide A, C and D could decrease the ALP activity and prevent the mineralization. To explore the utility in altering estrogen deficiency-induced bone loss, aged female mice were subcutaneous injected KLH-DKK1 peptides once every two weeks. Serum were separated to acess the biomarker of bone turnover and femurs were dissected to assess bone densitometry and histochemistry. Bone densitometry showed that the increases in bone formation with peptide treatment resulted in significant increases in bone mineral density (BMD). These increases, expressed as percent changes from baseline were 11 to 21 percentage points higher than those found in the sham-injection group, which indicated that peptide injection treatment significantly abrogated the suppressing effect of estrogen deficiency-induced bone loss. Taken together, these preclinical results suggest that peptides injection-mediated inhibition of DKK1 represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis. |
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