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Full Length Article | Open Access

Mapk7 deletion in chondrocytes causes vertebral defects by reducing MEF2C/PTEN/AKT signaling

Chengzhi Wua,1,, Hengyu Liua,1, Dongmei Zhongc,1, Xiaoming Yangd, Zhiheng Liaoa, Yuyu Chena, Shun Zhanga, Deying Sue, Baolin Zhanga, Chuan Lib, Liru Tianb, Caixia Xub( ), Peiqiang Sua( )
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
Research Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
Guangdong Provincial Key Laboratory of Proteomics and State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China

1 These authors contributed equally to this work.

Peer review under responsibility of Chongqing Medical University.

Show Author Information

Abstract

Mutation of the MAPK7 gene was related to human scoliosis. Mapk7 regulated the development of limb bones and skulls in mice. However, the role of MAPK7 in vertebral development is still unclear. In this study, we constructed Col2a1-cre; Mapk7f/f transgenic mouse model to delete Mapk7 in cartilage, which displayed kyphosis and osteopenia. Mechanistically, Mapk7 loss decreased MEF2C expression and thus activated PTEN to oppose PI3K/AKT signaling in vertebral growth plate chondrocytes, which impaired chondrocyte hypertrophy and attenuated vertebral ossification. In vivo, systemic pharmacological activation of AKT rescued impaired chondrocyte hypertrophy and alleviated mouse vertebral defects caused by Mapk7 deficiency. Our study firstly clarified the mechanism by which MAPK7 was involved in vertebral development, which might contribute to understanding the pathology of spinal deformity and provide a basis for the treatment of developmental disorders of the spine.

Keywords

PTENPI3K/AKTChondrocyte hypertrophyGrowth plateKyphosisMAPK7MEF2COsteopenia

References

1

Scaal M. Early development of the vertebral column. Semin Cell Dev Biol. 2016;49:83-91.
Crossref Google Scholar
2

Williams S, Alkhatib B, Serra R. Development of the axial skeleton and intervertebral disc. Curr Top Dev Biol. 2019;133:49-90.
Crossref Google Scholar
3

Mackie EJ, Ahmed YA, Tatarczuch L, et al. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol. 2008;40(1):46-62.
Crossref Google Scholar
4

Long F, Ornitz DM. Development of the endochondral skeleton. Cold Spring Harbor Perspect Biol. 2013;5(1):a008334.
Crossref Google Scholar
5

Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423(6937):332-336.
Crossref Google Scholar
6

Yang G, Zhu L, Hou N, et al. Osteogenic fate of hypertrophic chondrocytes. Cell Res. 2014;24(10):1266-1269.
Crossref Google Scholar
7

Zhou X, von der Mark K, Henry S, et al. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet. 2014;10(12):e1004820.
Crossref Google Scholar
8

Yang L, Tsang KY, Tang HC, et al. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci U S A. 2014;111(33):12097-12102.
Crossref Google Scholar
9

Hallett SA, Ono W, Ono N. Growth plate chondrocytes: skeletal development, growth and beyond. Int J Mol Sci. 2019;20(23):6009.
Crossref Google Scholar
10

Takeda S, Bonnamy JP, Owen MJ, et al. Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev. 2001;15(4):467-481.
Crossref Google Scholar
11

Nithianandarajah-Jones GN, Wilm B, Goldring CEP, et al. ERK5: structure, regulation and function. Cell Signal. 2012;24(11):2187-2196.
Crossref Google Scholar
12

Paudel R, Fusi L, Schmidt M. The MEK5/ERK5 pathway in health and disease. Int J Mol Sci. 2021;22(14):7594.
Crossref Google Scholar
13

Zhou T, Chen C, Xu C, et al. Mutant MAPK7-induced idiopathic scoliosis is linked to impaired osteogenesis. Cell Physiol Biochem. 2018;48(3):880-890.
Crossref Google Scholar
14

Gao W, Chen C, Zhou T, et al. Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis. Hum Mutat. 2017;38(11):1500-1510.
Crossref Google Scholar
15

Iezaki T, Fukasawa K, Horie T, et al. The MAPK Erk5 is necessary for proper skeletogenesis involving a Smurf-Smad-Sox9 molecular axis. Development. 2018;145(14):dev164004.
Google Scholar
16

Yang X, Zhong D, Gao W, et al. Conditional ablation of MAPK7 expression in chondrocytes impairs endochondral bone formation in limbs and adaptation of chondrocytes to hypoxia. Cell Biosci. 2020;10:103.
Crossref Google Scholar
17

Horie T, Fukasawa K, Yamada T, et al. Erk5 in bone marrow mesenchymal stem cells regulates bone homeostasis by preventing osteogenesis in adulthood. Stem Cell. 2022;40(4):411-422.
Crossref Google Scholar
18

Hall KC, Hill D, Otero M, et al. ADAM17 controls endochondral ossification by regulating terminal differentiation of chondrocytes. Mol Cell Biol. 2013;33(16):3077-3090.
Crossref Google Scholar
19

Rigueur D, Lyons KM. Whole-mount skeletal staining. Methods Mol Biol. 2014;1130:113-121.
Crossref Google Scholar
20

Laws N, Hoey A. Progression of kyphosis in mdx mice. J Appl Physiol (1985). 2004;97(5):1970-1977.
Crossref Google Scholar
21

Huang DW, Sherman BT, Tan Q, et al. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 2007;35(Web Server issue):W169-W175.
Crossref Google Scholar
22

Ran FA, Hsu PD, Wright J, et al. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8(11):2281-2308.
Crossref Google Scholar
23

Fleming A, Kishida MG, Kimmel CB, et al. Building the backbone: the development and evolution of vertebral patterning. Development. 2015;142(10):1733-1744.
Crossref Google Scholar
24

Ikegami D, Akiyama H, Suzuki A, et al. Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Development. 2011;138(8):1507-1519.
Crossref Google Scholar
25

Worby CA, Dixon JE. Pten. Annu Rev Biochem. 2014;83:641-669.
Crossref Google Scholar
26

Yang G, Sun Q, Teng Y, et al. PTEN deficiency causes dyschondroplasia in mice by enhanced hypoxia-inducible factor 1α signaling and endoplasmic reticulum stress. Development. 2008;135(21):3587-3597.
Crossref Google Scholar
27

Kato Y, Kravchenko VV, Tapping RI, et al. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J. 1997;16(23):7054-7066.
Crossref Google Scholar
28

Dy P, Wang W, Bhattaram P, et al. Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell. 2012;22(3):597-609.
Crossref Google Scholar
29

Arnold MA, Kim Y, Czubryt MP, et al. MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell. 2007;12(3):377-389.
Crossref Google Scholar
30

Scheuermann HW. The classic: kyphosis dorsalis juvenilis. Clin Orthop Relat Res. 1977;(128):5-7.
Crossref Google Scholar
31

Lowe TG, Line BG. Evidence based medicine: analysis of Scheuermann kyphosis. Spine. 2007;32(19 Suppl):S115-S119.
Crossref Google Scholar
32

Bradford DS, Brown DM, Moe JH, et al. Scheuermann’s kyphosis: a form of osteoporosis? Clin Orthop Relat Res. 1976(118):10-15.
Crossref Google Scholar
33

Damborg F, Engell V, Andersen M, et al. Prevalence, concordance, and heritability of Scheuermann kyphosis based on a study of twins. J Bone Joint Surg Am. 2006;88(10):2133-2136.
Crossref Google Scholar
34

Palazzo C, Sailhan F, Revel M. Scheuermann’s disease: an update. Jt Bone Spine. 2014;81(3):209-214.
Crossref Google Scholar
35

Ueta C, Iwamoto M, Kanatani N, et al. Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J Cell Biol. 2001;153(1):87-100.
Crossref Google Scholar
36

Ulici V, Hoenselaar KD, Gillespie JR, et al. The PI3K pathway regulates endochondral bone growth through control of hypertrophic chondrocyte differentiation. BMC Dev Biol. 2008;8:40.
Crossref Google Scholar
37

Hsieh SC, Chen NT, Lo SH. Conditional loss of PTEN leads to skeletal abnormalities and lipoma formation. Mol Carcinog. 2009;48(6):545-552.
Crossref Google Scholar
38

Kim JM, Yang YS, Park KH, et al. A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation. Nat Commun. 2020;11:2289.
Crossref Google Scholar
39

Yoshida CA, Yamamoto H, Fujita T, et al. Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev. 2004;18(8):952-963.
Crossref Google Scholar
40

Fujita T, Azuma Y, Fukuyama R, et al. Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling. J Cell Biol. 2004;166(1):85-95.
Crossref Google Scholar
41

Salhotra A, Shah HN, Levi B, et al. Mechanisms of bone development and repair. Nat Rev Mol Cell Biol. 2020;21(11):696-711.
Crossref Google Scholar
42

Loveridge CJ, van ’t Hof RJ, Charlesworth G, et al. Analysis of Nkx3.1:Cre-driven Erk5 deletion reveals a profound spinal deformity which is linked to increased osteoclast activity. Sci Rep. 2017;7:13241.
Crossref Google Scholar
43

Shu HS, Liu YL, Tang XT, et al. Tracing the skeletal progenitor transition during postnatal bone formation. Cell Stem Cell. 2021;28(12):2122-2136.e3.
Crossref Google Scholar
44

Ono N, Ono W, Nagasawa T, et al. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol. 2014;16(12):1157-1167.
Crossref Google Scholar
45

Mizuhashi K, Ono W, Matsushita Y, et al. Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature. 2018;563(7730):254-258.
Crossref Google Scholar
46

Chan CF, Seo E, Chen J, et al. Identification and specification of the mouse skeletal stem cell. Cell. 2015;160(1-2):285-298.
Crossref Google Scholar
47

Bobick BE, Matsche AI, Chen FH, et al. The ERK5 and ERK1/2 signaling pathways play opposing regulatory roles during chondrogenesis of adult human bone marrow-derived multipotent progenitor cells. J Cell Physiol. 2010;224(1):178-186.
Crossref Google Scholar
48

Stokes IA, Mente PL, Iatridis JC, et al. Enlargement of growth plate chondrocytes modulated by sustained mechanical loading. J Bone Joint Surg Am. 2002;84(10):1842-1848.
Crossref Google Scholar
49

Lee D, Erickson A, Dudley AT, et al. Mechanical stimulation of growth plate chondrocytes: previous approaches and future directions. Exp Mech. 2019;59(9):1261-1274.
Crossref Google Scholar
Genes & Diseases
Volume 11 Issue 2,
March 2024
Pages 964-977
DOI: 10.1016/j.gendis.2023.02.012
Cite this article:
Wu C, Liu H, Zhong D, et al. Mapk7 deletion in chondrocytes causes vertebral defects by reducing MEF2C/PTEN/AKT signaling. Genes & Diseases, 2024, 11(2): 964-977. https://doi.org/10.1016/j.gendis.2023.02.012

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Received: 07 November 2022
Revised: 17 January 2023
Accepted: 07 February 2023
Published: 24 March 2023
© 2023 The Authors.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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