Development of Craniofacial Biomineralization in Mice with Osteogenesis Imperfecta (OI)

Abstract

Osteogenesis imperfecta (OI), or “brittle bone disease,” is a rare autosomal dominant disorder characterized by mutations in the genes that encode the alpha 1 (COL1A1) and alpha 2 (COL1A2) chains of type I collagen, a significant component of bone. Misfolding of the mutated collagen polypeptides interfere with proper assembly of collagen chains, or the triple helical structures, leading to extreme skeletal fragility. OI manifests in a variety of types, with type I being the most mild and most common, and type III, the subject of this study, being more severe and more rare. Clinical manifestations of OI type III generally include a short stature, low bone mineral density (BMD), dental problems, hearing loss, and blue sclerae. In this study, we use a mouse model of OI type III to examine how mutations in type I collagen synthesis impact craniofacial biomineralization during postnatal growth.The homozygous recessive osteogenesis imperfecta murine (OIM) is a model of OI type III and is characterized by increased skeletal fractures, low postcranial BMD, osteopenia, progressive skeletal deformities, and small body size. Wild type mice (WT) and OIM littermates (n≥3/genotype) were micro‐CT scanned at weaning (4 weeks) and adulthood (16 weeks). BMD at three regions of interest (ROI) within the mouse skull was measured using Bruker CTAnalyzer software. ROIs were chosen based on the amount of load during mastication, and included the temporomandibular joint (TMJ), the parietal bone (1mm from the sagittal suture), and the anterior maxilla at the incisal alveolus. Mann‐Whitney U‐tests (α=0.05) were used to compare BMD values between the genotypes for each ROI.At weaning, OIM mice had significantly lower BMD values (g.cm−3 CaHA) than their wild type littermates at the TMJ (0.39 vs 0.58), parietal bone (0.35 vs 0.64), and anterior maxilla (0.53 vs 0.85). These statistical differences persist into adulthood. This decrease in BMD reflects decreased deposition of CaHA due to an abnormal collagen framework in the craniofacial skeleton of OIM mice. Ongoing efforts will expand this analysis to quantify the development of BMD at additional regions within the craniofacial skeleton.Support or Funding InformationThis research was supported by an Indiana University Collaborative Research Grant and the Ralph W. and Grace Showalter Trust.