Britney Stewart Dr. Evans Genetics of Osteoporosis: Can a New Perspective of Osteoporosis Lead to New Treatments? Britney Stewart Dr. Evans

Osteoporosis Osteoporosis is a disease that causes deterioration of the bone and bone tissue and low bone mineral density (BMD) Environmental factors influence osteoporosis susceptibility but it is believed that BMD is genetically influenced as well

Suspect Genes Polymorphisms in numerous genes could control Osteoporosis the VDR gene LRP5 and SOST gene TNFSF11 gene ESR1 gene

Identification Large-scale genome wide association studies (GWAS) scans the entire genome to locate genes that are associated with the disease Candidate gene approach identify pre-specified genetic loci that contribute to the risk for osteoporosis Twin/family studies those with effected lineages have genomes screened to find linkages between certain chromosomes and osteoporosis-related genes

VDR Vitamin D Receptor Regulates calcium homeostasis in the bone Single nucleotide polymorphisms (SNPs) in intron 8 and the 3’- untranslated region are associated with a lower BMD

LRP5 and SOST Key players in the Wnt signaling pathway Wnt signaling pathway regulates bone density through the LRP5 The Wnt protein and a frizzled receptor interact with LRP5 to initiate Wnt β-catenin signaling  β-catenin moves to the nucleus to attach to transcription factors Activation of this pathway leads to an increase in bone formation When SOST is present the Wnt protein is unable to interact with LRP5 and a decrease in bone formation occurs

Wnt Signaling Pathway (Urano & Inoue)

LRP5 Protein Structure (Urano & Inoue)

TNFSF11 Encodes RANK receptor and RANKL protein RANK receptor on osteoclasts and osteoclast precursors regulate differentiation and function RANKL is the protein that interacts with RANK Stimulates bone resorption by activating RANK signaling and promotes maturation of pre-osteoclasts Polymorphisms regulate but their mechanisms are still being investigated

ESR1 Estrogen 1 receptor Correlation between BMD and the variable number of repeats (VNTR) within the ESR1 promoter regions (Urano & Inoue) Presence of polymorphisms result in osteoporosis Urano, Inoue. 2014. Genetics of osteoporosis. Biochem Bioph Res Co 452: 287-293.