Are biological agents toxic to human chondrocytes and osteocytes?

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Abstract

Purpose

The aim of the present study is to investigate the effects of biological agents (BAs) on human chondrocytes and osteocytes in vitro.

Methods

Primary cell cultures obtained from gonarthrosis patients were divided into four groups, two of which were designated as control cultures of chondrocyte and osteocyte, and the other two groups were exposed to BAs administered via the culture medium. Cultured cells were characterized by immunophenotyping. Before and after administration of the agents, the cultures were observed by inverted and environmental scanning electron microscopy (ESEM). The number of live cells and the proliferation rate were monitored by MTT assay.

Results

Rituximab and adalimumab were the least toxic agents to chondrocytes, whereas adalimumab and etanercept were to osteocytes.

Conclusion

During periods of intense active inflammation, the concentration of the preferred BAs after inhibition of inflammation needs to be emphasized when their effects on cartilage and bone tissue are considered at the cellular level if the clinical practice is to continue.

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Most cited references 34

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Mesenchymal stem cells.

J Minguell, A Erices, P Conget (2001)

Within the bone marrow stroma there exists a subset of nonhematopoietic cells referred to as mesenchymal stem or mesenchymal progenitor cells. These cells can be ex vivo expanded and induced, either in vitro or in vivo, to terminally differentiate into osteoblasts, chondrocytes, adipocytes, tenocytes, myotubes, neural cells, and hematopoietic-supporting stroma. The multipotential of these cells, their easy isolation and culture, as well as their high ex vivo expansive potential make these cells an attractive therapeutic tool. In this work we will review the information dealing with the biology of mesenchymal progenitors as it has been revealed mainly by ex vivo studies performed with bone marrow-derived cells. The discussed topics include, among others, characteristics of mesenchymal progenitors, evidence for the existence of a vast repertoire of uncommitted and committed progenitors both in the bone marrow and in mesenchymal tissues, a diagram for their proliferative hierarchy, and comments on mobilization, microenvironment, and clinical use of mesenchymal progenitors. Despite the enormous data available at molecular and cellular levels, it is evident that a number of fundamental questions still need to be resolved before mesenchymal progenitors can be used for safe and effective clinical applications in the context of both cell and gene therapies.

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Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab.

Hiroki Mitoma, Takahiko Horiuchi, Hiroshi Tsukamoto … (2008)

Three anti-tumor necrosis factor alpha (anti-TNFalpha) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNFalpha monoclonal antibodies, while etanercept is engineered from human type II TNF receptors. In spite of all 3 agents' equal efficacy for RA, both infliximab and adalimumab are effective for other diseases such as Crohn's disease and Wegener's granulomatosis, while etanercept is not. We undertook this study to understand the different clinical effects of these anti-TNFalpha agents by analyzing their biologic activities on transmembrane TNFalpha. Jurkat T cells stably expressing an uncleavable form of transmembrane TNFalpha were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNFalpha, 2) complement-dependent cytotoxicity (CDC), 3) antibody-dependent cell-mediated cytotoxicity (ADCC) by using peripheral blood mononuclear cells, and 4) outside-to-inside (reverse) signal transduction through transmembrane TNFalpha estimated by apoptosis and cell cycle analysis using flow cytometry. All of the anti-TNFalpha agents bound to transmembrane TNFalpha. Infliximab and adalimumab exerted almost equal CDC activities, while etanercept showed considerably lower activity. ADCC activities were almost equal among these 3 agents. Adalimumab and infliximab induced apoptosis and cell cycle arrest in transmembrane TNFalpha-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNFalpha. Three different anti-TNF agents showed different biologic effects on transmembrane TNFalpha. This finding suggests that CDC and outside-to-inside signals by anti-TNFalpha antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.

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Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept.

C Shen, G Assche, S. Colpaert … (2005)

Adalimumab, a fully human monoclonal antibody to tumour necrosis factor, was recently introduced for therapy of Crohn's disease. Since induction of apoptosis of inflammatory cells is thought to be an important mechanism of action of the antitumour necrosis factor monoclonal antibody infliximab, we studied the induction of apoptosis of activated peripheral blood monocytes by adalimumab. Apoptosis was analysed at the levels of the cell membrane, mitochondria and DNA by flow cytometry. We found that both adalimumab and infliximab induced apoptosis in cultured monocytes, while etanercept did not. Apoptosis induction was caspase-dependent and detectable already after 2 h. The production of interleukin-10 and interleukin-12 by monocytes was down-regulated significantly by adalimumab and infliximab but not by etanercept, while levels of soluble tumour necrosis factor in monocyte cultures were down-regulated by all three reagents. These data show that both adalimumab and infliximab affect monocyte cytokine production and induce apoptosis of activated monocytes. Our findings will have to be further correlated to therapeutic efficacy of these antitumour necrosis factor reagents.

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Author and article information

Contributors

Mehmet Isyar: +9053 3722 7971 , misyar2003@yahoo.com

Bulent Bilir: bulentbilir@yahoo.com

Ibrahim Yilmaz: ibrahimyilmaz77@yahoo.com

Selami Cakmak: selamcakmak@yahoo.com

Duygu Yasar Sirin: duygusirin@nku.edu.tr

Aliye Yildirim Guzelant: aliyeguzelant@gmail.com

Mahir Mahirogullari: mahirogullari@yahoo.com

Journal

Journal ID (nlm-ta): J Orthop Surg Res

Journal ID (iso-abbrev): J Orthop Surg Res

Title: Journal of Orthopaedic Surgery and Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1749-799X

Publication date (Electronic): 30 July 2015

Publication date PMC-release: 30 July 2015

Publication date Collection: 2015

Volume: 10

Electronic Location Identifier: 118

Affiliations

[ ]Department of Orthopaedic and Traumatology, School of Medicine, Istanbul Medipol University, Bagcilar, 34214 Istanbul, Turkey

[ ]Department of Internal Medicine, School of Medicine, Namik Kemal University, 59100 Tekirdag, Turkey

[ ]Department of Pharmacovigilance and Rational Drug Use Team, Republic of Turkey, Ministry of Health, State Hospital, 59100 Tekirdag, Turkey

[ ]Department of Orthopaedic and Traumatology, Haydarpasa Training Hospital, Gulhane Military Medical Academy, 34668, Istanbul, Turkey

[ ]Faculty of Science, Department of Molecular Biology and Genetics, Namik Kemal University, 59100 Tekirdag, Turkey

[ ]Department of Physical Medicine and Rehabilitation, School of Medicine, Namik Kemal University, 59100 Tekirdag, Turkey

Article

Publisher ID: 264

DOI: 10.1186/s13018-015-0264-y

PMC ID: 4520184

SO-VID: 14c511ce-db5a-4aee-86e8-545c50069b2f

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 April 2015

Date accepted : 16 July 2015

Custom metadata

ScienceOpen disciplines: Surgery

Keywords: biological agents,chondrotoxicity,osteotoxicity,primary cell culture

Data availability:

ScienceOpen disciplines: Surgery

Keywords: biological agents, chondrotoxicity, osteotoxicity, primary cell culture

Are biological agents toxic to human chondrocytes and osteocytes?

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Abstract

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Methods

Results

Conclusion

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25th European Students' Conference

Most cited references 34

Mesenchymal stem cells.

Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab.

Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept.

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