Breaking More Than Bones: Systemic Marker Dysregulation in a Mouse Model of Osteogenesis Imperfecta

This thesis asks how a single change in type I collagen can unsettle organ biology outside the skeleton. Using the Brtl mouse, I examined the cerebellum at eighteen months and the liver and kidney at twelve months with a mixed toolkit: routine histology, Picrosirius in bright field and polarized light, Picro Mallory, quantitative whole-field image analysis in CellProfiler, targeted immunolabeling with optical density and cell counts, and transmission electron microscopy. In the cerebellum the three layers remain in place, yet the molecular and internal granular layers hold fewer cells, and small hemorrhages appear in males. Collagen signals are weaker in meninges and choroid plexus. Endothelial readouts suggest sex specific barrier remodeling: ZO-1, VE-cadherin and VEGF shift in opposite directions in males and females. Autophagy markers point to different control points by sex. In males, p62 is lower while LC3B rises and cathepsin B falls, consistent with brisk autophagosome formation and limited degradative capacity; in females, LC3B is lower while cathepsin B and p62 patterns fit reduced initiation with relatively active clearance. PINK1 and Parkin are both reduced, with PINK1 more affected in females and Parkin in males. Mitochondrial and redox indicators converge on organelle strain: cytochrome c increases, COX4 falls, SOD2 and NRF2 increase, and GPX4 is broadly reduced. Calbindin, a calcium buffer, increases in males and stays near baseline in females. In the viscera, related themes recur with different weight. In the liver, p62 and LC3B rise in males and fall in females; p53 increases in both sexes and PARP1 is markedly higher in males. Electron microscopy in male liver shows thinner, disorganized collagen fibrils, dilated rough endoplasmic reticulum and enlarged mitochondria. Picro Mallory confirms a thinning of endothelial associated fibrous structures in liver and a milder change in kidney. Renal autophagy shifts are modest, while p53 and PARP1 again separate by sex. Together, the data support a matrix to mitochondria cascade buffered by antioxidant responses, selective autophagy, mitophagy and DNA repair, with failure points set by tissue and sex.