Bone Abstracts

Osteogenesis imperfect (OI) is an inheritable bone disease with low bone mass, fragility, deformity and multiple fractures in skeletal tissues. Modulation of Wnt signalling components reportedly alleviates excessive bone and joint remodelling in various skeletal disorders. This study is undertaken to explore whether loss of Wnt inhibitor Dickkopf-1 (Dkk1) action affects bone formation or skeletal homeostasis in OI. In clinical vignettes, OI patients had severe osteoporosis (T-score) in spines and hips in association with high serum Dkk1 levels compared to normal subjects. Treatment with Dkk1 antibodies or recombinant Wnt3a increased the expression of Runx2, collagen 1α2 and osteocalcin and mineralized nodule formation in primary bone-marrow mesenchymal stem cells from OI patients underwent osteotomy. In experimental OI models, oim mice had lower bone mass and higher serum Dkk1 levels than WT mice. Administration of nanoparticles with phosphorothioate antisense oligonucleotide for Dkk1 decreased serum and bone tissue Dkk1 expression in OI mice. Loss of Dkk1 function increased bone mineral density and trabecular bone volume and reduced cortical bone porosity in OI mice. Dkk1 antisense oligonucleotide treatment increased mineral acquisition in skeletal tissue and promoted osteogenic gene expression and ex vivo osteoblastogenesis in primary bone-marrow mesenchymal cells. Knockdown of Dkk1 reduced the OI promotion of osteoclast surface and ex vivo osteoclast differentiation and resorption capacity of primary bone-marrow macrophage precursor cells in OI mice. Taken together, high Dkk1 level impedes bone formation activities and bone homeostasis in OI patients. Dkk1 interference has therapeutic potential for ameliorating the OI-mediated excessive bone remodelling and skeletal deterioration.