ADAM-12 (Meltrin α) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage

Aiko Okada, Satsuki Mochizuki, Taku Yatabe, Tokuhiro Kimura, Takayuki Shiomi, Yoshinari Fujita, Hideo Matsumoto, Atsuko Sehara-Fujisawa, Yukihide Iwamoto, Yasunori Okada

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Objective. ADAMs are a gene family of multifunctional proteins. We undertook this study to determine which ADAM species is up-regulated in osteoarthritic (OA) cartilage and to examine its pathobiologic function. Methods. Expression of the 13 different metalloproteinase-type ADAMs was screened by reverse transcription-polymerase chain reaction (PCR), and expression levels of prototype membrane-anchored ADAM-12 (ADAM-12m) were determined by real-time PCR. ADAM-12m expression in articular cartilage was examined by in situ hybridization, immunohistochemistry, and immunoblotting. Chondrocytes were used for functional analyses of ADAM-12m. Results. ADAM-12m was selectively expressed in 87% of OA cartilage, and the expression level was significantly higher in OA cartilage than in normal cartilage. In situ hybridization showed that OA chondrocytes were responsible for the expression. ADAM-12m was immunolocalized on the membranes of OA chondrocytes, and its immunoreactivity correlated directly with the Mankin score and with degrees of chondrocyte cloning and proliferation. Immunoblotting analysis of OA chondrocytes demonstrated an active form of ADAM-12m. ADAM-12m expression in OA chondrocytes was selectively enhanced by transforming growth factor β (TGFβ), which also induced chondrocyte proliferation and degradation of insulin-like growth factor binding protein 5 (IGFBP-5). TGFβ-induced chondrocyte proliferation was inhibited by suppression of IGF-1 signaling. In addition, TGFβ-induced chondrocyte proliferation, chondrocyte cloning in agarose gel culture, and digestion of IGFBP-5 were inhibited with ADAM inhibitor, anti-ADAM-12 antibody, and small interfering RNA for ADAM-12. Conclusion. These data suggest a novel function of ADAM-12m in chondrocyte proliferation and cloning in OA cartilage through enhanced bioavailability of IGF-1 from the IGF-1-IGFBP-5 complex by selective IGFBP-5 digestion.

Original languageEnglish
Pages (from-to)778-789
Number of pages12
JournalArthritis and Rheumatism
Volume58
Issue number3
DOIs
Publication statusPublished - 2008 Mar

Fingerprint

Insulin-Like Growth Factor Binding Protein 5
Chondrocytes
Cartilage
Transforming Growth Factors
Insulin-Like Growth Factor I
Organism Cloning
Immunoblotting
In Situ Hybridization
Membranes
Articular Cartilage
Metalloproteases
Sepharose
Small Interfering RNA
Biological Availability
Proteolysis
Reverse Transcription
Real-Time Polymerase Chain Reaction
Digestion

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

ADAM-12 (Meltrin α) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage. / Okada, Aiko; Mochizuki, Satsuki; Yatabe, Taku; Kimura, Tokuhiro; Shiomi, Takayuki; Fujita, Yoshinari; Matsumoto, Hideo; Sehara-Fujisawa, Atsuko; Iwamoto, Yukihide; Okada, Yasunori.

In: Arthritis and Rheumatism, Vol. 58, No. 3, 03.2008, p. 778-789.

Research output: Contribution to journalArticle

Okada, A, Mochizuki, S, Yatabe, T, Kimura, T, Shiomi, T, Fujita, Y, Matsumoto, H, Sehara-Fujisawa, A, Iwamoto, Y & Okada, Y 2008, 'ADAM-12 (Meltrin α) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage', Arthritis and Rheumatism, vol. 58, no. 3, pp. 778-789. https://doi.org/10.1002/art.23262
Okada, Aiko ; Mochizuki, Satsuki ; Yatabe, Taku ; Kimura, Tokuhiro ; Shiomi, Takayuki ; Fujita, Yoshinari ; Matsumoto, Hideo ; Sehara-Fujisawa, Atsuko ; Iwamoto, Yukihide ; Okada, Yasunori. / ADAM-12 (Meltrin α) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage. In: Arthritis and Rheumatism. 2008 ; Vol. 58, No. 3. pp. 778-789.
@article{438dd9a8676840f4ac6367f5469124b1,
title = "ADAM-12 (Meltrin α) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage",
abstract = "Objective. ADAMs are a gene family of multifunctional proteins. We undertook this study to determine which ADAM species is up-regulated in osteoarthritic (OA) cartilage and to examine its pathobiologic function. Methods. Expression of the 13 different metalloproteinase-type ADAMs was screened by reverse transcription-polymerase chain reaction (PCR), and expression levels of prototype membrane-anchored ADAM-12 (ADAM-12m) were determined by real-time PCR. ADAM-12m expression in articular cartilage was examined by in situ hybridization, immunohistochemistry, and immunoblotting. Chondrocytes were used for functional analyses of ADAM-12m. Results. ADAM-12m was selectively expressed in 87{\%} of OA cartilage, and the expression level was significantly higher in OA cartilage than in normal cartilage. In situ hybridization showed that OA chondrocytes were responsible for the expression. ADAM-12m was immunolocalized on the membranes of OA chondrocytes, and its immunoreactivity correlated directly with the Mankin score and with degrees of chondrocyte cloning and proliferation. Immunoblotting analysis of OA chondrocytes demonstrated an active form of ADAM-12m. ADAM-12m expression in OA chondrocytes was selectively enhanced by transforming growth factor β (TGFβ), which also induced chondrocyte proliferation and degradation of insulin-like growth factor binding protein 5 (IGFBP-5). TGFβ-induced chondrocyte proliferation was inhibited by suppression of IGF-1 signaling. In addition, TGFβ-induced chondrocyte proliferation, chondrocyte cloning in agarose gel culture, and digestion of IGFBP-5 were inhibited with ADAM inhibitor, anti-ADAM-12 antibody, and small interfering RNA for ADAM-12. Conclusion. These data suggest a novel function of ADAM-12m in chondrocyte proliferation and cloning in OA cartilage through enhanced bioavailability of IGF-1 from the IGF-1-IGFBP-5 complex by selective IGFBP-5 digestion.",
author = "Aiko Okada and Satsuki Mochizuki and Taku Yatabe and Tokuhiro Kimura and Takayuki Shiomi and Yoshinari Fujita and Hideo Matsumoto and Atsuko Sehara-Fujisawa and Yukihide Iwamoto and Yasunori Okada",
year = "2008",
month = "3",
doi = "10.1002/art.23262",
language = "English",
volume = "58",
pages = "778--789",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - ADAM-12 (Meltrin α) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage

AU - Okada, Aiko

AU - Mochizuki, Satsuki

AU - Yatabe, Taku

AU - Kimura, Tokuhiro

AU - Shiomi, Takayuki

AU - Fujita, Yoshinari

AU - Matsumoto, Hideo

AU - Sehara-Fujisawa, Atsuko

AU - Iwamoto, Yukihide

AU - Okada, Yasunori

PY - 2008/3

Y1 - 2008/3

N2 - Objective. ADAMs are a gene family of multifunctional proteins. We undertook this study to determine which ADAM species is up-regulated in osteoarthritic (OA) cartilage and to examine its pathobiologic function. Methods. Expression of the 13 different metalloproteinase-type ADAMs was screened by reverse transcription-polymerase chain reaction (PCR), and expression levels of prototype membrane-anchored ADAM-12 (ADAM-12m) were determined by real-time PCR. ADAM-12m expression in articular cartilage was examined by in situ hybridization, immunohistochemistry, and immunoblotting. Chondrocytes were used for functional analyses of ADAM-12m. Results. ADAM-12m was selectively expressed in 87% of OA cartilage, and the expression level was significantly higher in OA cartilage than in normal cartilage. In situ hybridization showed that OA chondrocytes were responsible for the expression. ADAM-12m was immunolocalized on the membranes of OA chondrocytes, and its immunoreactivity correlated directly with the Mankin score and with degrees of chondrocyte cloning and proliferation. Immunoblotting analysis of OA chondrocytes demonstrated an active form of ADAM-12m. ADAM-12m expression in OA chondrocytes was selectively enhanced by transforming growth factor β (TGFβ), which also induced chondrocyte proliferation and degradation of insulin-like growth factor binding protein 5 (IGFBP-5). TGFβ-induced chondrocyte proliferation was inhibited by suppression of IGF-1 signaling. In addition, TGFβ-induced chondrocyte proliferation, chondrocyte cloning in agarose gel culture, and digestion of IGFBP-5 were inhibited with ADAM inhibitor, anti-ADAM-12 antibody, and small interfering RNA for ADAM-12. Conclusion. These data suggest a novel function of ADAM-12m in chondrocyte proliferation and cloning in OA cartilage through enhanced bioavailability of IGF-1 from the IGF-1-IGFBP-5 complex by selective IGFBP-5 digestion.

AB - Objective. ADAMs are a gene family of multifunctional proteins. We undertook this study to determine which ADAM species is up-regulated in osteoarthritic (OA) cartilage and to examine its pathobiologic function. Methods. Expression of the 13 different metalloproteinase-type ADAMs was screened by reverse transcription-polymerase chain reaction (PCR), and expression levels of prototype membrane-anchored ADAM-12 (ADAM-12m) were determined by real-time PCR. ADAM-12m expression in articular cartilage was examined by in situ hybridization, immunohistochemistry, and immunoblotting. Chondrocytes were used for functional analyses of ADAM-12m. Results. ADAM-12m was selectively expressed in 87% of OA cartilage, and the expression level was significantly higher in OA cartilage than in normal cartilage. In situ hybridization showed that OA chondrocytes were responsible for the expression. ADAM-12m was immunolocalized on the membranes of OA chondrocytes, and its immunoreactivity correlated directly with the Mankin score and with degrees of chondrocyte cloning and proliferation. Immunoblotting analysis of OA chondrocytes demonstrated an active form of ADAM-12m. ADAM-12m expression in OA chondrocytes was selectively enhanced by transforming growth factor β (TGFβ), which also induced chondrocyte proliferation and degradation of insulin-like growth factor binding protein 5 (IGFBP-5). TGFβ-induced chondrocyte proliferation was inhibited by suppression of IGF-1 signaling. In addition, TGFβ-induced chondrocyte proliferation, chondrocyte cloning in agarose gel culture, and digestion of IGFBP-5 were inhibited with ADAM inhibitor, anti-ADAM-12 antibody, and small interfering RNA for ADAM-12. Conclusion. These data suggest a novel function of ADAM-12m in chondrocyte proliferation and cloning in OA cartilage through enhanced bioavailability of IGF-1 from the IGF-1-IGFBP-5 complex by selective IGFBP-5 digestion.

UR - http://www.scopus.com/inward/record.url?scp=40549091250&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40549091250&partnerID=8YFLogxK

U2 - 10.1002/art.23262

DO - 10.1002/art.23262

M3 - Article

C2 - 18311789

AN - SCOPUS:40549091250

VL - 58

SP - 778

EP - 789

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 3

ER -