Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts
Qian Zhang, … , Charles R. Farber, Thomas L. Clemens
Qian Zhang, … , Charles R. Farber, Thomas L. Clemens
Published April 1, 2021
Citation Information: J Clin Invest. 2021;131(7):e142580. https://doi.org/10.1172/JCI142580.
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Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

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.

Authors

Qian Zhang, Larry D. Mesner, Gina M. Calabrese, Naomi Dirckx, Zhu Li, Angela Verardo, Qian Yang, Robert J. Tower, Marie-Claude Faugere, Charles R. Farber, Thomas L. Clemens

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Figure 1

Genetically regulated alterations in MARK3 splicing colocalize with an eBMD GWAS locus on chr 14 at 103.4 Mbp.

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Genetically regulated alterations in MARK3 splicing colocalize with an e...
(A) The levels of all exons of the canonical MARK3 transcript are affected by the rs11623869 genotype. (B) An example of exon 7 shows increased normalized RNA-Seq read counts in individuals homozygous for the nonreference alleles (TT) of rs11623869. (C) Reads mapping to intron 5 are influenced by rs11623869 genotype. (D) Normalized intron 5 reads were increased in individuals homozygous for the nonreference alleles (TT) of rs11623869. (E) sQTL influencing the excision of intron 5 in GTEx (version 8) pancreas tissue colocalizes with an eBMD GWAS locus on chr 14 at 103.4 Mbp. (F) sQTL influencing the excision of intron 5 in GTEx (version 8) salivary gland tissue colocalizes with an eBMD GWAS locus on chr 14 at 103.4 Mbp. (G) sQTL influencing the excision of intron 5 in GTEx (version 8) testis tissue colocalizes with an eBMD GWAS locus on chr 14 at 103.4 Mbp. (H) Cell lines with at least 1 rs11623869 T allele have a larger number of reads mapping to intron 5. (I) Schematic of the exons formed in intron 5 of MARK3. PPH4, colocalization posterior probability of hypothesis 4, which states that a single causal variant drives both the sQTL and eBMD association.