Amyloid β peptide promotes bone formation by regulating Wnt/β-catenin signaling and the OPG/RANKL/RANK system.

Background Amyloid beta peptide (A beta) is involved in osteoporosis, but the effects of A beta on osteoblast and bone formation remain unclear. In this study, we investigated the effect of A beta on bone formation. Methods An animal model of osteoporosis was established by ovariectomy in C57BL/6 mice. The mice received intraperitoneal injection of A beta. The effect of A beta on the osteogenic differentiation of human bone marrow stromal stem cells (hBMSCs) and differentiation of both pre-osteoblasts and pre-osteoclasts in a co-culture system were investigated. Results In the animal study, intraperitoneal injection of A beta for 8 weeks promoted early and late osteogenic differentiation of hBMSCs. A beta treatment significantly elevated osterix(+) (osteoblastic) cells but decreased TRAP(+) cells (osteoclasts) in the distal femur bone. In vitro study showed that A beta treatment significantly enhanced matrix mineralization and osteogenic markers (Runx2 and osteocalcin). A beta treatment activated Wnt/beta-catenin signaling in hBMSCs. The effect of A beta was blocked by DKK1 (a Wnt/beta-catenin inhibitor) treatment. In the co-culture system, A beta treatment significantly increased the ALP activities of MC3T3-E1 cells (pre-osteoblasts) but reduced the TRAP(+) RAW264.7 cells (pre-osteoclasts). A beta treatment upregulated TCF1 and OPG proteins in MC3T3-E1 cells. A beta treatment upregulated I kappa B-alpha but downregulated NFATc1protein in RAW264.7 cells. These effects were blocked by XAV-939 (a Wnt signaling antagonist), and then rescued by additional Wnt3a (a Wnt agonist). Conclusion A beta treatment simultaneously promoted osteogenic differentiation via Wnt/beta-catenin signaling, and inhibited osteoclasts differentiation via the OPG/RANKL/RANK system, suggesting A beta is a positive regulator of osteoblast differentiation and bone formation.