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- Title
Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts.
- Authors
Qian Zhang; Mesner, Larry D.; Calabrese, Gina M.; Dirckx, Naomi; Zhu Li; Verardo, Angela; Yang, Qian; Tower, Robert J.; Faugere, Marie-Claude; Farber, Charles R.; Clemens, Thomas L.; Zhang, Qian; Li, Zhu
- Abstract
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.
- Subjects
SERINE/THREONINE kinases; NOTCH signaling pathway; OSTEOBLASTS; BONE density; CHROMOSOMES; BONE fractures; OSTEOBLAST metabolism; BONE metabolism; RESEARCH; GENETICS; BONES; ANIMAL experimentation; ANTHROPOMETRY; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; CELLULAR signal transduction; COMPARATIVE studies; TRANSFERASES; MICE
- Publication
Journal of Clinical Investigation, 2021, Vol 131, Issue 7, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI142580