Craniofacial Morphology of Juvenile Mice with Osteogenesis Imperfecta




Steele, Ashley T.


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Osteogenesis Imperfecta (OI) is a heritable connective tissue disorder affecting the synthesis and structure of type I collagen (Col1) due to autosomal dominant mutations in proa1(I) or proa2(I) collagen genes (COL1A1 and COL1A2). Clinical manifestations of the severe OI type III include bone fragility, reduced physical stature, and midface hypoplasia resulting in a "triangle face" phenotype. Current treatment options have low-success rates and focus primarily on alleviating symptoms through surgical interventions and pharmacologic use of antiresorptive drugs. The homozygous OI murine (OIM-/-) mouse model has a nonlethal, recessively inherited mutation of the COL1A2 gene and exhibits adult cranial and post-cranial phenotypes similar to humans with severe OI type III; however, the juvenile phenotype is unknown. The goals of this study are: (1) to determine if significant differences in craniofacial skeletal shape and size are present at the age of weaning (21 days/4 weeks) in the OIM-/- mice compared to the wild type (WT) and (2) to determine if these differences are still significant when adjusted for the allometric effects of body size. OIM-/- and WT littermates were weaned at 21 days and scanned in-vivo with a Skyscan 1176 micro-CT system. Craniofacial geometric landmarks were collected using 3D Slicer software and were subsequently used to calculate interlandmark distances (ILDs) and centroid sizes. ILDs were scaled against skull/mandible centroid size to account for the effect of overall body size on shape analyses. Mann-Whitney U-tests were used to compare both absolute and relative (scaled) ILDs between the genotypes. Craniomandibular centroid sizes and absolute linear distances (skull, rostrum, palate, and mandible lengths) demonstrate that the OIM-/- mice are smaller overall than their WT littermates. When scaled to centroid size, juvenile OIM-/- mice have a decrease in nasal length, mandibular diastema length, and basicranium but an increase in cranial vaults, midface heights, and both maxillary and mandibular toothrow lengths compared to WT mice. For a given skull length, OIM-/- mice have shorter faces in both the anteroposterior and dorsoventral dimensions. The morphometric changes seen in the juvenile OIM-/- mice replicate the "triangle face" and relative macrocephaly that is commonly seen in human pediatric populations with OI. This suggests that this mouse model can potentially be used to investigate the structural changes underlying the human OI phenotype and for potential therapeutic interventions, such as biomechanical loading, myostatin knock-out, and pharmaceutical therapies. Additionally, the results of this study can be used to inform future investigations of Col1 in craniofacial development. Continuing to evaluate the etiology of this disorder can lead to better treatment options to improve the quality of life for patients with OI, especially pediatric patients.