Top

Modern Rheumatology

Published in:

01-11-2013 | Original Article

Role of FK506 binding protein 5 (FKBP5) in osteoclast differentiation

Authors: Miho Kimura, Tatsuo Nagai, Reiko Matsushita, Atsushi Hashimoto, Toshiyuki Miyashita, Shunsei Hirohata

Published in: Modern Rheumatology | Issue 6/2013

Abstract

Objectives

We previously disclosed the enhanced expression of FK506 binding protein 5 (FKBP5) messenger RNA (mRNA) in bone marrow (BM) CD34⁺ cells in rheumatoid arthritis (RA), in which systemic osteoporosis takes place. Since BM CD34⁺ cells are precursors of osteoclasts, it is possible that FKBP5 overexpression might lead to osteoporosis by affecting osteoclastogenesis. We therefore explore the influences of FKBP5 in osteoclast differentiation.

Methods

Stable transfectants of RAW264.7 overexpressing murine FKBP5 gene were established. Osteoclast differentiation was induced by receptor activator of nuclear factor kappa B (NF-κB) ligand and was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and pit formation assay.

Results

FKBP5 transfectants of RAW264.7 generated higher numbers of TRAP-positive multinucleated cells with increased activity of pit formation on calcium phosphate-coated culture slides than mock transfectants. The enhancement of osteoclast differentiation of FKBP5 transfectants was only partially inhibited by N-acetyl l-cysteine. Finally, glucocorticoid enhanced FKBP5 mRNA expression as well as osteoclast differentiation of RAW264.7 cells in a dose-dependent manner.

Conclusions

These results indicate that FKBP5 promotes osteoclast differentiation by a mechanism distinct from NF-κB activation. Moreover, the data suggest that FKBP5 might play a role in bone destruction and development of osteoporosis in RA as well as in glucocorticoid-induced osteoporosis.

Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–61.PubMedCrossRef

Sambrook PN, Eisman JA, Champion GD, Yeates MG, Pocock NA, Eberl S. Determinants of axial bone loss in rheumatoid arthritis. Arthritis Rheum. 1987;30:721–8.PubMedCrossRef

Sinigaglia L, Nervetti A, Mela Q, Bianchi G, Del Puente A, Di Munno O, et al. A multicenter cross sectional study on bone mineral density in rheumatoid arthritis. Italian Study Group on Bone Mass in Rheumatoid Arthritis. J Rheumatol. 2000;27:2582–9.PubMed

Ross FP. RANKing the importance of measles virus in Paget’s disease. J Clin Invest. 2000;105:555–8.PubMedCrossRef

Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289:1504–8.PubMedCrossRef

Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390:175–9.PubMedCrossRef

Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165–76.PubMedCrossRef

Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000;106:1481–8.PubMedCrossRef

Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem. 1997;272:25190–4.PubMedCrossRef

10.

Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 1998;95:3597–602.PubMedCrossRef

11.

Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, et al. Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J. 2001;20:1271–80.PubMedCrossRef

12.

Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells. 1999;4:353–62.PubMedCrossRef

13.

Wong BR, Josien R, Lee SY, Vologodskaia M, Steinman RM, Choi Y. The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor. J Biol Chem. 1998;273:28355–9.PubMedCrossRef

14.

Hirohata S, Miura Y, Tomita T, Yoshikawa H, Ochi T, Chiorazzi N. Enhanced expression of mRNA for nuclear factor kappaB1 (p50) in CD34+ cells of the bone marrow in rheumatoid arthritis. Arthritis Res Ther. 2006;8:R54.PubMedCrossRef

15.

Hirohata S, Yanagida T, Nampei A, Kunugiza Y, Hashimoto H, Tomita T, et al. Enhanced generation of endothelial cells from CD34+ cells of the bone marrow in rheumatoid arthritis: possible role in synovial neovascularization. Arthritis Rheum. 2004;50:3888–96.PubMedCrossRef

16.

Nakamura N, Shimaoka Y, Tougan T, Onda H, Okuzaki D, Zhao H, et al. Isolation and expression profiling of genes upregulated in bone marrow-derived mononuclear cells of rheumatoid arthritis patients. DNA Res. 2006;13:169–83.PubMedCrossRef

17.

Matsushita R, Hashimoto A, Tomita T, Yoshitawa H, Tanaka S, Endo H, et al. Enhanced expression of mRNA for FK506-binding protein 5 in bone marrow CD34 positive cells in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:87–90.PubMed

18.

Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 2004;6:97–105.PubMedCrossRef

19.

Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621–63.PubMedCrossRef

20.

Blin-Wakkach C, Wakkach A, Rochet N, Carle GF. Characterization of a novel bipotent hematopoietic progenitor population in normal and osteopetrotic mice. J Bone Miner Res. 2004;19:1137–43.PubMedCrossRef

21.

Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, et al. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev. 1997;11:3482–96.PubMedCrossRef

22.

Sugatani T, Alvarez U, Hruska KA. PTEN regulates RANKL- and osteopontin-stimulated signal transduction during osteoclast differentiation and cell motility. J Biol Chem. 2003;278:5001–8.PubMedCrossRef

23.

Vaira S, Alhawagri M, Anwisye I, Kitaura H, Faccio R, Novack DV. RelA/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in mice. J Clin Invest. 2008;118:2088–97.PubMed

24.

Vermeer H, Hendriks-Stegeman BI, van der Burg B, van Buul-Offers SC, Jansen M. Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability. J Clin Endocrinol Metab. 2003;88:277–84.PubMedCrossRef

25.

Makkonen H, Kauhanen M, Paakinaho V, Jääskeläinen T, Palvimo JJ. Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers. Nucleic Acids Res. 2009;37:4135–48.PubMedCrossRef

26.

Paakinaho V, Makkonen H, Jääskeläinen T, Palvimo JJ. Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions. Mol Endocrinol. 2010;24:511–25.PubMedCrossRef

27.

Massey HM, Flanagan AM. Human osteoclasts derive from CD34-positive monocytes. Br J Haematol. 1999;106:167–70.PubMedCrossRef

28.

Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem. 2000;275:4858–64.PubMedCrossRef

29.

Kim HH, Lee DE, Shin JN, Lee YS, Jeon YM, Chung CH, et al. Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett. 1999;443:297–302.PubMedCrossRef

30.

Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3:889–901.PubMedCrossRef

31.

Takayanagi H, Kim S, Taniguchi T. Signaling crosstalk between RANKL and interferons in osteoclast differentiation. Arthritis Res. 2002;4(Suppl 3):S227–32.PubMedCrossRef

32.

Yamamoto A, Miyazaki T, Kadono Y, Takayanagi H, Miura T, Nishina H, et al. Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand. J Bone Miner Res. 2002;17:612–21.PubMedCrossRef

33.

Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem. 2000;275:31155–61.PubMedCrossRef

34.

Miyazaki T, Katagiri H, Kanegae Y, Takayanagi H, Sawada Y, Yamamoto A, et al. Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts. J Cell Biol. 2000;148:333–42.PubMedCrossRef

35.

Zhang YH, Heulsmann A, Tondravi MM, Mukherjee A, Abu-Amer Y. Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem. 2001;276:563–8.PubMedCrossRef

36.

Miyauchi Y, Ninomiya K, Miyamoto H, Sakamoto A, Iwasaki R, Hoshi H, et al. The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis. J Exp Med. 2010;207:751–62.PubMedCrossRef

37.

Wochnik GM, Rüegg J, Abel GA, Schmidt U, Holsboer F, Rein T. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem. 2005;280:4609–16.PubMedCrossRef

38.

Li H, Qian W, Weng X, Wu Z, Li H, Zhuang Q, et al. Glucocorticoid receptor and sequential P53 activation by dexamethasone mediates apoptosis and cell cycle arrest of osteoblastic MC3T3-E1 cells. PLoS ONE. 2012;7:e37030.PubMedCrossRef

39.

Thiele S, Ziegler N, Tsourdi E, De Bosscher K, Tuckermann JP, Hofbauer LC, et al. Selective glucocorticoid receptor modulation maintains bone mineral density in mice. J Bone Miner Res. 2012;27:2242–50.PubMedCrossRef

Title: Role of FK506 binding protein 5 (FKBP5) in osteoclast differentiation
Authors: Miho Kimura
Tatsuo Nagai
Reiko Matsushita
Atsushi Hashimoto
Toshiyuki Miyashita
Shunsei Hirohata
Publication date: 01-11-2013
Publisher: Springer Japan
Published in: Modern Rheumatology / Issue 6/2013
Print ISSN: 1439-7595
Electronic ISSN: 1439-7609
DOI: https://doi.org/10.1007/s10165-012-0809-4

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2013

Serum chemokine levels as prognostic markers in patients with early systemic sclerosis: a multicenter, prospective, observational study

A case of Behçet’s disease developing after poststreptococcal acute glomerulonephritis

Upregulation of VEGF expression is associated with accumulation of HIF-1α in the skin of naïve scleroderma patients

The roles of IFN-γ versus IL-17 in pathogenic effects of human Th17 cells on synovial fibroblasts

Subclinical cardiovascular target organ damage manifestations of ankylosing spondylitis in young adult patients

Post-surgical hemorrhagic infarction of the adrenal gland as the first clinical manifestation of antiphospholipid syndrome after 43 years of antibody-positivity

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials