GSE160415
RNA-seq Analysis of Wild Type and Mark3-/- mouse primary osteoblasts
Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture.  Genome wide association studies (GWAS) have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on Chromosome 14q32.32 alter splicing and expression of PAR-1a/MARK3, a conserved serine/threonine kinase known to regulate bioenergetics, cell division and polarity.  Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3 deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway.  Mark3 deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3 deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively.  Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass. Overall design: Primary osteoblast mRNA profiles of control and 24h deletion of Mark3 treatment