ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo

Hisako Ishizuka, Verõnica García-Palacios, Ganwei Lu, Mark A. Subler, Heju Zhang, Christina S. Boykin, Sun Jin Choi, Liena Zhao, Kenneth Patrene, Deborah L. Galson, Harry C. Blair, Tamer M. Hadi, Jolene J. Windle, Noriyoshi Kurihara, G. David Roodman

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)-ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-ÎB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease.

Original languageEnglish (US)
Pages (from-to)169-181
Number of pages13
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume26
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

Fingerprint

Osteoclasts
Bone and Bones
Knockout Mice
Tumor Necrosis Factor-alpha
TNF Receptor-Associated Factor 6
Hip Prosthesis
Synovial Membrane
Bone Remodeling
Metabolic Bone Diseases
In Vitro Techniques
Osteogenesis
Transgenic Mice
Rheumatoid Arthritis
Fibrosis
Phenotype

Keywords

  • ADAM8
  • ADHESION MOLECULES
  • CELL DIFFERENTIATION
  • OSTEOCLAST
  • TRANSGENIC/KNOCKOUT MICE

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo. / Ishizuka, Hisako; García-Palacios, Verõnica; Lu, Ganwei; Subler, Mark A.; Zhang, Heju; Boykin, Christina S.; Choi, Sun Jin; Zhao, Liena; Patrene, Kenneth; Galson, Deborah L.; Blair, Harry C.; Hadi, Tamer M.; Windle, Jolene J.; Kurihara, Noriyoshi; Roodman, G. David.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 26, No. 1, 01.2011, p. 169-181.

Research output: Contribution to journalArticle

Ishizuka, H, García-Palacios, V, Lu, G, Subler, MA, Zhang, H, Boykin, CS, Choi, SJ, Zhao, L, Patrene, K, Galson, DL, Blair, HC, Hadi, TM, Windle, JJ, Kurihara, N & Roodman, GD 2011, 'ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo', Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, vol. 26, no. 1, pp. 169-181. https://doi.org/10.1002/jbmr.199
Ishizuka, Hisako ; García-Palacios, Verõnica ; Lu, Ganwei ; Subler, Mark A. ; Zhang, Heju ; Boykin, Christina S. ; Choi, Sun Jin ; Zhao, Liena ; Patrene, Kenneth ; Galson, Deborah L. ; Blair, Harry C. ; Hadi, Tamer M. ; Windle, Jolene J. ; Kurihara, Noriyoshi ; Roodman, G. David. / ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo. In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011 ; Vol. 26, No. 1. pp. 169-181.
@article{2f073c7b9a964308bdf2869c4259d6bf,
title = "ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo",
abstract = "ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)-ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-{\^I}B, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease.",
keywords = "ADAM8, ADHESION MOLECULES, CELL DIFFERENTIATION, OSTEOCLAST, TRANSGENIC/KNOCKOUT MICE",
author = "Hisako Ishizuka and Ver{\~o}nica Garc{\'i}a-Palacios and Ganwei Lu and Subler, {Mark A.} and Heju Zhang and Boykin, {Christina S.} and Choi, {Sun Jin} and Liena Zhao and Kenneth Patrene and Galson, {Deborah L.} and Blair, {Harry C.} and Hadi, {Tamer M.} and Windle, {Jolene J.} and Noriyoshi Kurihara and Roodman, {G. David}",
year = "2011",
month = "1",
doi = "10.1002/jbmr.199",
language = "English (US)",
volume = "26",
pages = "169--181",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo

AU - Ishizuka, Hisako

AU - García-Palacios, Verõnica

AU - Lu, Ganwei

AU - Subler, Mark A.

AU - Zhang, Heju

AU - Boykin, Christina S.

AU - Choi, Sun Jin

AU - Zhao, Liena

AU - Patrene, Kenneth

AU - Galson, Deborah L.

AU - Blair, Harry C.

AU - Hadi, Tamer M.

AU - Windle, Jolene J.

AU - Kurihara, Noriyoshi

AU - Roodman, G. David

PY - 2011/1

Y1 - 2011/1

N2 - ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)-ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-ÎB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease.

AB - ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)-ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-ÎB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease.

KW - ADAM8

KW - ADHESION MOLECULES

KW - CELL DIFFERENTIATION

KW - OSTEOCLAST

KW - TRANSGENIC/KNOCKOUT MICE

UR - http://www.scopus.com/inward/record.url?scp=78650964948&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650964948&partnerID=8YFLogxK

U2 - 10.1002/jbmr.199

DO - 10.1002/jbmr.199

M3 - Article

C2 - 20683884

AN - SCOPUS:78650964948

VL - 26

SP - 169

EP - 181

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 1

ER -