Fragilitas ossium (fro/fro) in the mouse: A model for a recessively inherited type of osteogenesis imperfecta

Abstract

The fragilitas ossium (fro/fro) mutation in the mouse has been demonstrated to have clinical, radiographic and morphologic manifestations similar to those which arise in autosomal recessive forms of osteogenesis imperfecta (OI) occurring in humans. Approximately 90% of mutant offspring in the mouse were perinatally lethal with clinical and roentgenographic findings similar to those of OI type II subgroup A in humans. The 10% of mutant mice surviving follow a course very similar to severe progressively deforming OI type III. In surviving mice, there is progressive fore-limb and hind-limb bowing in the absence of a high fracture frequency.

Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels

“…There are at least five mouse models for osteogenesis imperfecta. Two of these models are natural mouse mutants (Chipman et al, 1993;Sillence et al, 1993) and the exact molecular defect has been characterized in one of them (Chipman et al, 1993). The other naturally occurring OI mouse is clinically similar to OI type III, but the molecular defect has not been defined (Sillence et al, 1993).…”

“…Two of these models are natural mouse mutants (Chipman et al, 1993;Sillence et al, 1993) and the exact molecular defect has been characterized in one of them (Chipman et al, 1993). The other naturally occurring OI mouse is clinically similar to OI type III, but the molecular defect has not been defined (Sillence et al, 1993). One of the mouse models generated in a laboratory contains a retrovirus in the first intron of the gene for the ~1 chain of type I procollagen, which in homozygous mice caused a lack of the ~1 chain in most tissues and death in utero (see Bonadio et al, 1990).…”

Osteogenesis Imperfecta

“…A high percentage of mutant pups die in the perinatal period with radiographic findings similar to a severe recessive OI type II. The surviving mice have progressive deformity but reduced fracture frequency (Sillence et al, 1993). The underlying mutation is a deletion in the sphingomyelin phosphodiesterase 3 (Smpd3) gene (Aubin et al, 2005) which was recently shown to be a positive regulator of mineralization in in vitro osteoblast cultures (Khavandgar et al, 2011).…”

Mechanism of Mineralization of Collagen‐Based Connective Tissues

“…It was recently discovered that a mouse model of osteogenesis imperfecta, the fro/fro mouse (for fragilitas ossifium [226]), rather than having a defect in type I collagen like the majority of the other osteogenesis imperfecta pre-clinical models, is due to a defect in neutral sphingomyelin phosphodiesterase 3 [227]. This enzyme is a member of a large superfamily of magnesium-dependent phosphohydrolases, it may play a role in signaling but its function in bone is unknown.…”