Absolute and Relative Morphometric Differences in the Craniofacial Skeleton of OIM-/- Mice and Wild-Type Littermates

Purpose: Osteogenesis Imperfecta (OI, or “Brittle Bone Disease”) is a disorder caused by genetic point mutations in COL1A1/COL1A2 which affect the synthesis of type I collagen (Col1). Humans with the severe type III OI exhibit increased susceptibility to skeletal fractures and shortened stature, as well as cranial dysmorphologies and dental malocclusions. Mouse models of Col1 defects report postcranial phenotypes similar to those seen in humans, with a limited number of studies reporting alterations to cranial and dental integrity. This project tests the hypothesis that the reduced craniofacial dimensions reported in both humans and mice with Col1 defects are linked to an overall reduction in body size. Methods: The homozygous OI murine (OIM-/-) is a mouse strain with a nonlethal recessively inherited mutation of the COL1A2 gene. Wild-type (WT) and OIM-/- littermates were weaned at 21d and raised until adult (16 weeks). 3D morphometric landmarks were collected from serial in-vivo µCT scans at 4, 10, and 16 weeks using etdips software. Past 2.17 software was used to Procrustes-transform (rotate and translate) the landmark data, and to calculate interlandmark distances (ILDs) and centroid sizes. ILDs were scaled against skull/mandible centroid size and skull/mandible length to account for the effect of size. Mann-Whitney U tests (α=0.05) were used to compare centroid sizes and both absolute and relative (scaled) ILDs between the genotypes. Results: When comparing absolute morphometric distances, adult OIM-/- mice have shorter skulls, basicrania, palates, mandibles, and toothrows. However, OIM-/-mice are smaller overall than their WT littermates as measured by both body mass and craniomandibular centroid sizes. When the effects of size are accounted for, the trend for interlandmark distances in WT mice to be greater than those in OIM-/- mice is significantly reduced or even reversed. For example, when scaled to centroid size, no significant difference exists between WT and OIM-/- mice in skull, basicranial, or mandibular length. OIM-/- mice have a relatively short midface, short nasal bones, tall mandibular corpora and long mandibular toothrows. Conclusions: These findings underscore the importance of size and scaling in morphometric analyses. The deleterious effect of Col1 mutations on global skeletal dimensions, in combination with localized morphometric changes, may underlie the facial phenotype seen in human patients with OI type III. Attempts to identify these localized changes should first account for the restricted growth and small body sizes present in individuals with OI.