Craniofacial Bone Mineral Density During Growth in Mice with Osteogenesis Imperfecta (OI)

Abstract

Osteogenesis imperfecta (OI or “brittle bone” disease) is a genetic connective tissue defect which results in fragile bones and increased fracture rates. OI type III is the severe form of this disorder, resulting from mutations affecting the formation of type I collagen, the structural protein of bone. Defects in the collagen framework of developing bones lead to improper biomineralization and are thought to underlie the gross structural abnormalities seen in patients with OI, such as midfacial hypoplasia, dental malocclusions, and macrocephaly. Low bone mineral density (BMD) in the post-cranial skeleton and brittle teeth have been reported in human patients with OI as well as murine models of the disorder, yet little is known about craniofacial biomineralization in OI. Typically, skeletal mineralization is responsive to the strain environment throughout growth. The aim of this study is to investigate longitudinal changes in craniofacial BMD in a mouse model of OI type III, and to quantify BMD in regions both proximal and distal to the biomechanical forces generated by feeding behaviors. We hypothesize that mice with OI will have lower BMD at weaning than their unaffected littermates, and will maintain this lower BMD throughout growth. We also hypothesize that both genotypes will demonstrate the absolute highest levels of BMD in regions proximal to the bite point, due to the biomechanical forces generated by feeding. To test these hypotheses, we used the homozygous recessive OI murine (OIM-/-), a mouse strain with a COL1A2 mutation that is a model for OI type III, and their unaffected wild-type (WT) littermates. BMD was measured using in-vivo micro-CT scans at weeks 4 (weaning), 10 (adolescence) and 16 (skeletal maturity) using Bruker CTAnalyzer software. BMD was measured in 8 regions of interest encompassing the neurocranium, facial skeleton, and mandible. BMD values were compared between genotypes via Mann-Whitney U test. In general, this study found there is a trend for OIM mice to have lower BMD values in the craniofacial skeleton as compared to WT mice from weaning through skeletal maturity. OIM mice had significantly (p <0.05) lower BMD than WT mice in all 8 regions during week 4. No significant differences were found in BMD between the genotypes during week 10, possible due to low sample sizes at this time point. At week 16, significant differences (p <0.05) were found in BMD at the parietal bone, mandibular symphysis, and maxillary incisor regions between the genotypes, and weak significant differences (p = 0.07) were found in BMD at the temporomandibular joint region. Additionally, absolute BMD for both genotypes (OIM and WT) tended to be higher within facial and mandibular regions proximal to the bite point compared to the neurocranium at skeletal maturity. Currently, there is no cure for OI, but pharmaceutical interventions (e.g. bisphosphonates) focus on increasing BMD to reduce fracture rates. A better understanding of craniofacial mineralization patterns in OI patients could assist in the timing and implementation of these treatments.