Brittle, but not boring: a fresh look at osteogenesis imperfecta type V

Bone tissue homeostasis relies on a strict balance between bone resorption by osteoclasts and bone formation by osteoblasts. Studies of animal models with impaired bone formation or resorption have unraveled novel mechanisms controlling skeletal homeostasis. Osteogenesis imperfecta (OI), also called brittle bone disease, is a heterogeneous group of rare bone disorders associated with low bone mass and bone fragility. Patients with OI are classified into different types, or forms, based on the severity of the disease (mild to severe) and the mutated genes involved. Most OI cases affect the osteoblast lineage and result from pathologic variants of type I collagen (type I–IV), while other forms are associated with defective regulatory mechanisms directing collagen synthesis, bone mineralization, or osteoblast differentiation (type V–XXIII). OI type V is an autosomal dominant form of OI not associated with collagen type I mutations, but displaying osteoblastic bone formation deficit and hyperplastic callus appearance following fractures.1 At the genetic level, mutations in the interferon-induced transmembrane protein 5 (IFITM5) gene were demonstrated to be responsible for this disease. IFITM5 encodes for a type II transmembrane protein also named BRIL (bone-restricted IFITM-like) that is palmitoylated and localized at the plasma membrane.2,3 IFITM5 is mainly expressed in the osteoblast lineage and participates in osteoblast maturation and matrix mineralization in cellular models.2,3 However, inactivation of IFITM5 or overexpression of WT IFITM5 in mice did not lead to any bone phenotype.4,5 In fact, most OI type V patients are characterized by the same point mutation (ie, c.-14C>T) in IFITM5 mRNA 5′ untranslated region (UTR), which results in the production of a novel IFITM5 protein, called MALEP-IFTM5, harboring an additional five amino acids on its N-terminal. Toward mechanistic understanding of the IFITM5 mutation, several in vivo approaches in mice were designed. In contrast to the WT protein, transgenic expression of the mutant MALEP-IFITM5 under the Collagen α1 (Col1a1) promotor led to perinatal lethality with delayed mineralization, bone deformities, and spontaneous fractures.5 Similarly, a knock-in mouse model in which the c.-14C>T mutation was introduced in the Ifitm5 locus resulted in embryonic lethality with major skeletal abnormalities and decreased expression of the osteoblast marker genes Sost, Bglap, and Ibsp.6,7 However, the early lethality of the knock-in and transgenic c.-14C>T models has limited our understanding of OI type V pathologic mechanisms at the postnatal and adult stage.6

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