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Mol Cell Biol. 2019 May 28;39(12). pii: e00012-19. doi: 10.1128/MCB.00012-19. Print 2019 Jun 15.

Unexpected Role of Matrix Gla Protein in Osteoclasts: Inhibiting Osteoclast Differentiation and Bone Resorption.

Author information

1
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
2
The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
3
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China lixuxjtu@163.com shufangw@hotmail.com.

Abstract

Matrix Gla protein (MGP) is an extracellular protein responsible for inhibiting mineralization. MGP inhibits osteoblast mineralization and bone formation by regulating the deposition of bone matrix. However, Mgp-/- mice display an osteopenic phenotype. To explain this contradiction, we investigated the role of MGP in osteoclastogenesis, the other side of bone remodeling. We found that MGP expression is markedly increased by osteoclastic commitment. Osteoclast differentiation and bone resorption are accelerated by MGP depletion while suppressed by MGP overexpression. The in vivo results confirmed its inhibitory role in osteoclastogenesis by the administration of Cre-dependent FLEX-On recombinant MGP-AAV to LysM Cre mice. Furthermore, we found that the expression and nuclear translocation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), are under the control of MGP. MGP loss results in elevation of intracellular Ca2+ flux. Vitronectin-induced activation of Src/Rac1 is magnified in the absence of MGP but reduced when MGP is overexpressed. Inhibition of Src activation or NFATc1 nuclear import rescues the increased osteoclastogenesis induced by MGP deficiency. These observations (i) establish, for the first time to our knowledge, that MGP plays an essential role in osteoclast differentiation and function, (ii) enrich the current knowledge of MGP function, and (iii) indicate the potential of MGP as a therapeutic target for low-bone-mass disorders.

KEYWORDS:

MGP; bone loss; osteoclast differentiation; osteoclastogenesis

PMID:
30988158
PMCID:
PMC6549463
[Available on 2019-11-28]
DOI:
10.1128/MCB.00012-19

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