Erk1 Positively Regulates Osteoclast Differentiation and Bone Resorptive Activity

Yongzheng He,Jin Yuan,Yaling Liu,Shi Chen,Karl Staser,Xiaohua Wu,Steven D Rhodes,Su-Jung Park,Xianlin Yang,Feng-Chun Yang,Xiaohong Li,Li Jiang,Jose Alberola-Ila

doi:10.1371/journal.pone.0024780

Yongzheng He, Jin Yuan + Show 11 more

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https://doi.org/10.1371/journal.pone.0024780

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Abstract

The extracellular signal-regulated kinases (ERK1 and 2) are widely-expressed and they modulate proliferation, survival, differentiation, and protein synthesis in multiple cell lineages. Altered ERK1/2 signaling is found in several genetic diseases with skeletal phenotypes, including Noonan syndrome, Neurofibromatosis type 1, and Cardio-facio-cutaneous syndrome, suggesting that MEK-ERK signals regulate human skeletal development. Here, we examine the consequence of Erk1 and Erk2 disruption in multiple functions of osteoclasts, specialized macrophage/monocyte lineage-derived cells that resorb bone. We demonstrate that Erk1 positively regulates osteoclast development and bone resorptive activity, as genetic disruption of Erk1 reduced osteoclast progenitor cell numbers, compromised pit formation, and diminished M-CSF-mediated adhesion and migration. Moreover, WT mice reconstituted long-term with Erk1−/− bone marrow mononuclear cells (BMMNCs) demonstrated increased bone mineral density as compared to recipients transplanted with WT and Erk2−/− BMMNCs, implicating marrow autonomous, Erk1-dependent osteoclast function. These data demonstrate Erk1 plays an important role in osteoclast functions while providing rationale for the development of Erk1-specific inhibitors for experimental investigation and/or therapeutic modulation of aberrant osteoclast function.

Highlights

Normal bone physiology, as well as bone repair following injury, depends upon the productive and destructive interactions between osteoblasts and osteoclasts, whereby osteoblast-mediated bone production repairs localized defects created by osteoclasts
Multinucleated osteoclasts are continuously formed from the monocyte/macrophage lineage of hematopoietic cells [2,3], and osteoclastogenesis and normal osteoclast function depend upon multiple cytokines and growth factors, including macrophage colony stimulating factor (M-CSF), receptor activator for nuclear factor kappa-B ligand (RANKL), and transforming growth factor beta (TGFb) [4,5,6]
Deletion of Erk1 or Erk2 in bone marrow mononuclear cells (BMMNCs) and cultured osteoclasts PCR was conducted to assay the presence of the Erk1 null allele (Erk12/2), Mx1Cre transgene, and flanking loxP (Erk2flox/flox) alleles

Summary

Introduction

As well as bone repair following injury, depends upon the productive and destructive interactions between osteoblasts and osteoclasts, whereby osteoblast-mediated bone production repairs localized defects created by osteoclasts. Multinucleated osteoclasts are continuously formed from the monocyte/macrophage lineage of hematopoietic cells [2,3], and osteoclastogenesis and normal osteoclast function depend upon multiple cytokines and growth factors, including macrophage colony stimulating factor (M-CSF), receptor activator for nuclear factor kappa-B ligand (RANKL), and transforming growth factor beta (TGFb) [4,5,6]. These factors near-ubiquitously induce phosphorylation of Erk and Erk2 [4,5,6]. Alterations in the MAPK/ERK1/2 cascade contribute to cardio-facio-cutaneous syndrome (CFC), Noonan syndrome, LEOPARD syndrome, and Neurofibromatosis type 1 These pathophysiological observations suggest roles for ERK1 and ERK2 in human skeletal development [7,8,9]

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