Invention Novelty: The Johns Hopkins researchers have developed
BTKO mice having floxed alleles for both
Bmp1 and
Tll1, such that they can be conditionally knocked out either temporally, postnatally, or in a tissue-specific, non-lethal manner and have overcome issues of functional redundancy.
Value Proposition: Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by dominant mutations in the collagen I genes COL1A1/COL1A2, whereas rarer recessive OI is often caused by mutations in genes encoding collagen I-interacting proteins. Recently, mutations in the gene for the proteinase bone morphogenetic 1 (BMP1) were reported in two recessive OI families. BMP1 and the closely related proteinase mammalian tolloid-like 1 (mTLL1) being co-expressed in various tissues, including bone, and have overlapping activities that include biosynthetic processing of procollagen precursors into mature collagen monomers. However, early lethality of
Bmp1- and
Tll1-null mice has precluded use of such models for careful study of in vivo roles of their protein products. This technology is the establishment of a novel animal model that avoids barriers of
Bmp1−/− and
Tll1−/− lethality and issues of functional redundancy.
Technical Details: The JHU researchers employ novel mouse strains with floxed
Bmp1 and
Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers of
Bmp1−/− and
Tll1 −/− lethality and issues of functional redundancy. Bones of the conditionally null mice are dramatically weakened and brittle, with spontaneous fractures—defining features of OI. Additional skeletal features include osteomalacia, thinned/porous cortical bone, reduced processing of procollagen and dentin matrix protein 1, remarkably high bone turnover and defective osteocyte maturation that is accompanied by decreased expression of the osteocyte marker and Wnt-signaling inhibitor sclerostin, and by marked induction of canonical Wnt signaling. The novel animal model presented here provides new opportunities for in-depth analyses of in vivo roles of BMP1-like proteinases in bone and other tissues, and for their roles, and for possible therapeutic interventions, in OI.
