Low-density Lipoprotein Receptor-related Protein 5 (LRP5)-deficient Rats Have Reduced Bone Mass and Abnormal Development of the Retinal Vasculature

Human patients carrying homozygous loss-of-function mutations in the low-density lipoprotein receptor related protein 5 (LRP5) develop osteoporosis pseudoglioma (OPPG), a syndrome characterized by early-onset low bone mass and vision problems caused by abnormal vasculature of the eye. Lrp5-deficient mice have been created and are valuable models for OPPG, however rat models have not been previously developed. Work in several fields suggests that rats have advantages over mice in modeling human physiology. In addition, their larger organs relative to mice, provide increased tissue sample size and easier surgical manipuations, while requiring similar laboratory housing and husbandry. We used CRISPR/Cas9-mediated genetic engineering to create three strains of LRP5-deficient rats. We found that they modelled the low bone mass seen in their human and mouse counterparts. Facilitated by their increased size relatively to mice, we also carried out detailed assessment of ocular vascularization and found that the superficial retinal vasculature is sparse and disorganized with decreases vascularized area, vessel length and branch point density. Extensive exudates suggest increased vessel permeability. These rat models should be useful for further studies of the role of Wnt signaling in bone and retina development and research on treatment of osteoporosis and familial exudative vitroretinopathy.