Trabecular Bone Phenotype in Lysyl Oxidase Isoform Knockout Mice

OBJECTIVES: Lysyl oxidases constitute a family of enzymes responsible for the formation of cross links in collagen and elastin. The importance of collagen in the structural and mechanical properties of bone has led us to investigate the hypothesis that the absence of one or more of these enzymes could lead to a significant bone phenotype. This phenotype could resemble osteoporosis or diabetic bone disease. METHODS: Bones from 12-week old mice (8 males and 6 females) with the genotype LOX+/-, LOXL1 -/- were analyzed. 16 wild type mice (8 males and 8 females) were used as controls. micro-CT was used to analyze the trabecular and cortical bone structure in distal metaphysis and mid-diaphysis regions, respectively, of the left femur. The femora were subsequently tested to failure in torsion. Lower arm bones were used for cross-link analysis. Two way factor ANOVA was used for statistical analysis with P value less than 0.05 for significant differences. RESULTS: micro-CT analysis of the trabecular bone in distal metaphysis of the knockouts showed decreased relative bone volume, connectivity density and mineral density and increased trabecular spacing. Cortical bone in the mid-diaphysis region of the knockouts showed decreased relative bone volume and mineral density and increased cortical thickness and polar moment of inertia. Mechanical testing data showed increased torsional strength in the knockout mice. Cross link analysis showed that the total number of LOX-catalyzed aldehydes was significantly lower in the knockout mice. Correlation analysis showed that the decrease in hydroxylysine aldehyde (DHNL) in the knockout mice is correlated with a decrease in connectivity density (0.62). CONCLUSIONS: LOX+/- LOXL1-/-mice develop a significant bone phenotype characterized by porosity and spacing between the trabeculae. This could predispose them to microfracture and to be easily resorbed during bone turnover. DE14066 and DE11004