Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts
| Autor: | Angela R Verardo, Zhu Li, Qian Yang, Robert J. Tower, Naomi Dirckx, Thomas L. Clemens, Charles R. Farber, Gina M. Calabrese, Marie Claude Faugere, Qian Zhang, Larry D. Mesner |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases JAG1 Cell signaling Cell division Notch signaling pathway Biology Protein Serine-Threonine Kinases Bone and Bones 03 medical and health sciences Mice 0302 clinical medicine Bone Density Animals HES1 Bone mineral Mice Knockout Osteoblasts Kinase Genetic Variation General Medicine Organ Size Chromosomes Mammalian Cell biology 030104 developmental biology 030220 oncology & carcinogenesis RNA splicing Research Article Signal Transduction |
| Zdroj: | J Clin Invest |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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