title: Human mesenchymal stem cells inhibit osteoclastogenesis through osteoprotegerin production.
abstract: OBJECTIVE
  Mesenchymal stem cells (MSCs) have been proposed to be a useful tool for treatment of rheumatoid arthritis (RA), not only because of their multipotency but also because of their immunosuppressive effect on lymphocytes, dendritic cells, and other proinflammatory cells. Since bone destruction caused by activated osteoclasts occurs in RA, we undertook the present study to investigate the effect of MSCs on osteoclast function and differentiation in order to evaluate their potential use in RA therapy.
  
  
  METHODS
  Human MSCs and peripheral blood mononuclear cells were cultured under cell-cell contact-free conditions with osteoclast induction medium. Differentiation into osteoclast-like cells was determined by tartrate-resistant acid phosphatase staining and expression of osteoclast differentiation markers.
  
  
  RESULTS
  The number of osteoclast-like cells was decreased and expression of cathepsin K and nuclear factor of activated T cells c1 (NF-ATc1) was down-regulated by the addition of either MSCs or a conditioned medium obtained from MSCs. Osteoprotegerin (OPG) was constitutively produced by MSCs and inhibited osteoclastogenesis. However, osteoclast differentiation was not fully recovered upon treatment with either anti-OPG antibody or OPG small interfering RNA, suggesting that OPG had only a partial role in the inhibitory effect of MSCs. Moreover, bone-resorbing activity of osteoclast-like cells was partially recovered by addition of anti-OPG antibody into the conditioned medium.
  
  
  CONCLUSIONS
  The present results indicate that human MSCs constitutively produce OPG, resulting in inhibition of osteoclastogenesis and expression of NF-ATc1 and cathepsin K in the absence of cell-cell contact. Therefore, we conclude that human MSCs exert a suppressive effect on osteoclastogenesis, which may be beneficial in inhibition of joint damage in RA.
authors.affiliation: First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Fukuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Oshita
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamaoka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Fukuyo
authors.forename: Koshiro
authors.initials: K
authors.lastname: Sonomoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Maeshima
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kurihara
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakano
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Saito
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Okada
authors.forename: Kenji
authors.initials: K
authors.lastname: Chiba
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D056657:Cathepsin K / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018920:Coculture Techniques; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009000:Monocytes; D050778:NFATC Transcription Factors / Q000096:biosynthesis; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053244:Osteoprotegerin / Q000096:biosynthesis*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012213:Rheumatic Fever / Q000628:therapy; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D007527:Isoenzymes; D050778:NFATC Transcription Factors; D053244:Osteoprotegerin; D034741:RNA, Small Interfering; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; C534130:CTSK protein, human; D056657:Cathepsin K