Talk 12
Presenter: Charles Farber
Thursday, 9:50am

Systems Genetics Identifies Bicc1 as a Novel Genetic Determinant of Bone Mass and Osteoblastogenesis

Brianne Ray¹, Larry Mesner¹, Eric Lum¹, Gina Calabrese¹, Elizabeth C. Bryda², Guanqing Wu³, Clifford J. Rosen⁴, Thomas L. Clemens⁵, and Charles R. Farber^1,6
1Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22911 ²Research Animal Diagnostic Laboratory, Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65201 ³Division of Genetic Medicine, School of Medicine, Vanderbilt University, Nashville, TN 37232 ⁴Maine Medical Center Research Institute, Scarborough, ME 04074 ⁵Department of Orthopaedic Surgery, Johns Hopkins School of Medicine, Baltimore, MD 21287 ⁶Departments of Medicine (Division of Cardiovascular Medicine) and Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22911

Osteoporosis is a complex disease of bone fragility that affects millions of individuals in the U.S. Here, we set out to identify novel genes influencing bone mineral density (BMD), a highly heritable osteoporosis-related trait. Specifically, our goal was to identify the gene responsible for Bmd43, a quantitative trait locus (QTL) in the mouse. Bmd43 is located on Chromosome 10 and harbors 351 genes. To narrow this list, we identified genes whose expression was regulated by a local expression QTL (eQTL) that was predicted to be causal for Bmd43. Bicaudal C homolog 1 (Bicc1), a putative RNA-binding protein, was the only gene fitting this criterion. Mice heterozygous for a Bicc1 null allele had decreased femoral BMD and cortical thickness, confirming that Bicc1 dosage influences bone mass. We began to determine how Bicc1 is involved in the regulation of BMD by evaluating its membership in a bone co-expression network. Bicc1 belonged to a co-expression module enriched for genes involved in the differentiation of bone-forming osteoblasts. Consistent with this observation, knockdown of Bicc1 impaired the differentiation of primary osteoblasts. In the co-expression network, Bicc1 was most strongly connected to the polycystic kidney disease 2 (Pkd2) gene and knockdown of Bicc1 decreased Pkd2 transcript levels. Pkd2 knockdown also decreased osteoblastogenesis. Overexpression of Pkd2 in Bicc1 null osteoblasts rescued impaired differentiation, whereas overexpression of Bicc1 in Pkd2 null osteoblasts did not, suggesting that Bicc1 acts upstream of Pkd2. This study identifies Bicc1 as a novel genetic determinant of BMD and osteoblastogenesis, possibly by regulating Pkd2 transcript levels.