| First Author | Zhang Q | Year | 2021 |
| Journal | J Clin Invest | Volume | 131 |
| Issue | 7 | PubMed ID | 33792563 |
| Mgi Jnum | J:305797 | Mgi Id | MGI:6709830 |
| Doi | 10.1172/JCI142580 | Citation | Zhang Q, et al. (2021) Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts. J Clin Invest 131(7) |
| abstractText | Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. 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/microtubule affinity regulating kinase 3 (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. |
