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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Research Article Bone biology

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 3

Mice lacking Mark3 in osteoblasts exhibit normal fat mass, but higher bone mass.

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Mice lacking Mark3 in osteoblasts exhibit normal fat mass, but higher bo...
(A) Growth curves for Mark3fl/fl;Oc-Cre and control mice (Mark3fl/fl) over 12 weeks (n = 5–6). (B) Body weight, (C) body length, and (D) gonadal fat mass of Mark3fl/fl;Oc-Cre and Mark3fl/fl mice at 12 weeks and 18 months of age (n = 5–6 for 12 weeks; n = 9–10 for 18 months). (E) Glucose tolerance test (GTT) and insulin tolerance test (ITT) in Mark3fl/fl and Mark3fl/fl;Oc-Cre mice at 12 weeks (n = 6–7). (F and G) Representative computer renderings of bone structure and quantitative analysis of the femoral trabecular (F) and cortical bone (G) generated from Mark3fl/fl and Mark3fl/fl;Oc-Cre mice at 12 weeks and 18 months old (n = 5–6 for 12 weeks; n = 9–10 for 18 months). (H) Representative stress-strain curves and stress-strain curves of Mark3fl/fl;Oc-Cre and Mark3fl/fl mice. (I) Ultimate moment, Young’s modulus, ultimate strain, ultimate stress, preyield energy, preyield strain, preyield stress and postyield energy as measured by 3-point bending test of the 12-week-old femur (n = 10). (J) Histomorphometric analysis of Mark3fl/fl and Mark3fl/fl;Oc-Cre mice at 12 weeks of age (n = 7–10). (K) Serum P1NP and CTX levels at 12 weeks (n = 10). Data are represented as mean ± SEM. *P < 0.05, Student’s t test between genotypes.