Pmepa1 induced by RANKL-p38 MAPK pathway has a novel role in osteoclastogenesis

Noboru Funakubo, Xianghe Xu, Toshio Kukita, Seiji Nakamura, Hiroshi Miyamoto, Akiko Kukita

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Osteoclasts are multinucleated cells formed by fusion of preosteoclasts (POCs) derived from cells of the monocyte/macrophage lineage. We have reported a culture system that supports the formation of POCs from stroma-depleted rat bone marrow cells. Global gene expression analysis of this culture system identified genes highly expressed in POCs. Here,wehave analyzed the expression and function of one of these highly expressed genes, prostate transmembrane protein androgen induced 1 (Pmepa1), a target of TGF-β and binds Nedd4 ubiquitin ligase, which plays a role in intracellular trafficking. We show here that the expression of Pmepa1 was strongly induced by RANKL in mouse bone marrow macrophage and in the osteoclast precursor cell line RAW-D. The expression of Pmepa1 was increased at 24 hr of culture, but was decreased at 72 hr. Pmepa1 protein was localized to intracellular vesicle membrnane of mononuclear cells, some of which were cathepsin-K positive. RANKL-induced expression of Pmepa1 was significantly reduced by inhibitors of p38 MAPK signaling. Pmepa1 siRNA suppressed the formation of osteoclasts in RAW-D cells, and inhibited the expression of cathepsinKand c-fos but not RANK. In addition, inhibition of Pmepa1 expression reduced the surface expression of RANK in RAW-D cells induced by RANKL. These results demonstrate that Pmepa1 is induced by RANK-p38 MAPK pathway signaling, and upregulates cell surface expression of RANK, suggesting that Pmepa1 plays a role in osteoclastogenesis and osteoclast signaling.

Original languageEnglish
Pages (from-to)3105-3118
Number of pages14
JournalJournal of cellular physiology
Volume233
Issue number4
DOIs
Publication statusPublished - Apr 1 2018

Fingerprint

p38 Mitogen-Activated Protein Kinases
Osteogenesis
Androgens
Prostate
Osteoclasts
Proteins
Somatostatin-Secreting Cells
Macrophages
Cell culture
Bone
Genes
Cells
Cathepsin K
Cell Fusion
Ligases
Ubiquitin
Systems Analysis
Gene expression
Bone Marrow Cells
Small Interfering RNA

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Pmepa1 induced by RANKL-p38 MAPK pathway has a novel role in osteoclastogenesis. / Funakubo, Noboru; Xu, Xianghe; Kukita, Toshio; Nakamura, Seiji; Miyamoto, Hiroshi; Kukita, Akiko.

In: Journal of cellular physiology, Vol. 233, No. 4, 01.04.2018, p. 3105-3118.

Research output: Contribution to journalArticle

Funakubo, Noboru ; Xu, Xianghe ; Kukita, Toshio ; Nakamura, Seiji ; Miyamoto, Hiroshi ; Kukita, Akiko. / Pmepa1 induced by RANKL-p38 MAPK pathway has a novel role in osteoclastogenesis. In: Journal of cellular physiology. 2018 ; Vol. 233, No. 4. pp. 3105-3118.
@article{4dc0470266924e4281006e0857a2e5f2,
title = "Pmepa1 induced by RANKL-p38 MAPK pathway has a novel role in osteoclastogenesis",
abstract = "Osteoclasts are multinucleated cells formed by fusion of preosteoclasts (POCs) derived from cells of the monocyte/macrophage lineage. We have reported a culture system that supports the formation of POCs from stroma-depleted rat bone marrow cells. Global gene expression analysis of this culture system identified genes highly expressed in POCs. Here,wehave analyzed the expression and function of one of these highly expressed genes, prostate transmembrane protein androgen induced 1 (Pmepa1), a target of TGF-β and binds Nedd4 ubiquitin ligase, which plays a role in intracellular trafficking. We show here that the expression of Pmepa1 was strongly induced by RANKL in mouse bone marrow macrophage and in the osteoclast precursor cell line RAW-D. The expression of Pmepa1 was increased at 24 hr of culture, but was decreased at 72 hr. Pmepa1 protein was localized to intracellular vesicle membrnane of mononuclear cells, some of which were cathepsin-K positive. RANKL-induced expression of Pmepa1 was significantly reduced by inhibitors of p38 MAPK signaling. Pmepa1 siRNA suppressed the formation of osteoclasts in RAW-D cells, and inhibited the expression of cathepsinKand c-fos but not RANK. In addition, inhibition of Pmepa1 expression reduced the surface expression of RANK in RAW-D cells induced by RANKL. These results demonstrate that Pmepa1 is induced by RANK-p38 MAPK pathway signaling, and upregulates cell surface expression of RANK, suggesting that Pmepa1 plays a role in osteoclastogenesis and osteoclast signaling.",
author = "Noboru Funakubo and Xianghe Xu and Toshio Kukita and Seiji Nakamura and Hiroshi Miyamoto and Akiko Kukita",
year = "2018",
month = "4",
day = "1",
doi = "10.1002/jcp.26147",
language = "English",
volume = "233",
pages = "3105--3118",
journal = "Journal of Cellular Physiology",
issn = "0021-9541",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Pmepa1 induced by RANKL-p38 MAPK pathway has a novel role in osteoclastogenesis

AU - Funakubo, Noboru

AU - Xu, Xianghe

AU - Kukita, Toshio

AU - Nakamura, Seiji

AU - Miyamoto, Hiroshi

AU - Kukita, Akiko

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Osteoclasts are multinucleated cells formed by fusion of preosteoclasts (POCs) derived from cells of the monocyte/macrophage lineage. We have reported a culture system that supports the formation of POCs from stroma-depleted rat bone marrow cells. Global gene expression analysis of this culture system identified genes highly expressed in POCs. Here,wehave analyzed the expression and function of one of these highly expressed genes, prostate transmembrane protein androgen induced 1 (Pmepa1), a target of TGF-β and binds Nedd4 ubiquitin ligase, which plays a role in intracellular trafficking. We show here that the expression of Pmepa1 was strongly induced by RANKL in mouse bone marrow macrophage and in the osteoclast precursor cell line RAW-D. The expression of Pmepa1 was increased at 24 hr of culture, but was decreased at 72 hr. Pmepa1 protein was localized to intracellular vesicle membrnane of mononuclear cells, some of which were cathepsin-K positive. RANKL-induced expression of Pmepa1 was significantly reduced by inhibitors of p38 MAPK signaling. Pmepa1 siRNA suppressed the formation of osteoclasts in RAW-D cells, and inhibited the expression of cathepsinKand c-fos but not RANK. In addition, inhibition of Pmepa1 expression reduced the surface expression of RANK in RAW-D cells induced by RANKL. These results demonstrate that Pmepa1 is induced by RANK-p38 MAPK pathway signaling, and upregulates cell surface expression of RANK, suggesting that Pmepa1 plays a role in osteoclastogenesis and osteoclast signaling.

AB - Osteoclasts are multinucleated cells formed by fusion of preosteoclasts (POCs) derived from cells of the monocyte/macrophage lineage. We have reported a culture system that supports the formation of POCs from stroma-depleted rat bone marrow cells. Global gene expression analysis of this culture system identified genes highly expressed in POCs. Here,wehave analyzed the expression and function of one of these highly expressed genes, prostate transmembrane protein androgen induced 1 (Pmepa1), a target of TGF-β and binds Nedd4 ubiquitin ligase, which plays a role in intracellular trafficking. We show here that the expression of Pmepa1 was strongly induced by RANKL in mouse bone marrow macrophage and in the osteoclast precursor cell line RAW-D. The expression of Pmepa1 was increased at 24 hr of culture, but was decreased at 72 hr. Pmepa1 protein was localized to intracellular vesicle membrnane of mononuclear cells, some of which were cathepsin-K positive. RANKL-induced expression of Pmepa1 was significantly reduced by inhibitors of p38 MAPK signaling. Pmepa1 siRNA suppressed the formation of osteoclasts in RAW-D cells, and inhibited the expression of cathepsinKand c-fos but not RANK. In addition, inhibition of Pmepa1 expression reduced the surface expression of RANK in RAW-D cells induced by RANKL. These results demonstrate that Pmepa1 is induced by RANK-p38 MAPK pathway signaling, and upregulates cell surface expression of RANK, suggesting that Pmepa1 plays a role in osteoclastogenesis and osteoclast signaling.

UR - http://www.scopus.com/inward/record.url?scp=85051814586&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051814586&partnerID=8YFLogxK

U2 - 10.1002/jcp.26147

DO - 10.1002/jcp.26147

M3 - Article

VL - 233

SP - 3105

EP - 3118

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

IS - 4

ER -