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Inflammatory factors in the circulation of patients with active rheumatoid arthritis stimulate osteoclastogenesis via endogenous cytokine production by osteoblasts

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Abstract

Summary

The combination of cytokines present in the circulation of patients with active rheumatoid arthritis might contribute to the generalized bone loss that commonly occurs in these patients, by directly inhibiting osteoblast proliferation and differentiation, but especially by enhancing endogenous cytokine (i.e., receptor activator of nuclear factor-kappa B ligand (RANKL) and interleukin-6 (IL)-6) production by osteoblasts, thereby stimulating osteoclastogenesis.

Introduction

Generalized bone loss, as occurs in patients with rheumatoid arthritis (RA), is related to elevated levels of circulating cytokines. Individual cytokines have deleterious effects on proliferation and differentiation of osteoblast cell lines, but little is known about the effect of the interaction between inflammatory factors in the circulation of patients with active RA on human osteoblast function, including their communication towards other bone cells. We investigated whether serum from patients with active RA enhances cytokine production by osteoblasts, thereby effectively altering osteoblast-stimulated osteoclastogenesis.

Methods

Serum was obtained from 20 patients with active RA (active RA sera) and from the same patients in clinical remission (remission RA sera). To determine osteoclastogenesis, RA serum-pretreated primary human osteoblast cultures were established in direct contact with human osteoclast precursors in the presence or absence of osteoprotegerin (OPG) or IL-6 inhibitor.

Results

Compared to remission RA sera, active RA sera inhibited osteoblast proliferation and differentiation in vitro as demonstrated by a reduced DNA content and gene expression of KI-67, collagen type 1, osteopontin, and osteocalcin. Active RA sera inhibited OPG expression and enhanced RANKL and IL-6 expression but did not alter IL-8 expression in osteoblasts. IL-1β, IL-17, and tumor necrosis factor-α (TNF-α) expression were undetectable. In coculture, active RA sera treatment of osteoblasts stimulated while addition of OPG or IL-6 inhibitory antibodies significantly reduced the number of osteoclasts.

Conclusion

Active RA sera contain circulating factors, likely cytokines and chemokines, that might contribute to bone loss by directly inhibiting osteoblast proliferation and differentiation, but especially, these factors modulate endogenous cytokine production by osteoblasts, thereby affecting osteoclastogenesis.

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Acknowledgments

We thank Dr. Veerle Stouten for collecting RA serum, Dr. Teun J. de Vries and Ton Schoenmaker for technical support regarding the osteoclastogenesis assay, and Dr. Behrouz Zandieh Doulabi for primer design and technical support. This research was funded by the European Commission through MOVE-AGE, an Erasmus Mundus Joint Doctorate program (2011–2015).

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Move Research Institute Amsterdam, Gustav Mahlerlaan 3004, 1081 LA, Amsterdam, The Netherlands

    J. L. Pathak, J. Klein-Nulend & A. D. Bakker

  2. Skeletal Biology and Engineering Research Center, KU Leuven, Herestraat 49, 3000, Leuven, Belgium

    J. L. Pathak, P. Verschueren & F. P. Luyten

  3. Department of Clinical Chemistry, VU University Medical Center, Move Research Institute Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    N. Bravenboer

  4. Department of Rheumatology, VU University Medical Center, Move Research Institute Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    W. F. Lems

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  1. J. L. Pathak
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Correspondence to J. Klein-Nulend.

Additional information

J. Klein-Nulend and A.D. Bakker shared last authorship and contributed equally to this manuscript.

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Pathak, J.L., Bravenboer, N., Verschueren, P. et al. Inflammatory factors in the circulation of patients with active rheumatoid arthritis stimulate osteoclastogenesis via endogenous cytokine production by osteoblasts. Osteoporos Int 25, 2453–2463 (2014). https://doi.org/10.1007/s00198-014-2779-1

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