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T‐cell cytokine induction of BMP‐2 regulates human mesenchymal stromal cell differentiation and mineralization
Author(s) -
Rifas Leonard
Publication year - 2006
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20933
Subject(s) - mesenchymal stem cell , stromal cell , microbiology and biotechnology , osteoblast , bone morphogenetic protein 2 , alkaline phosphatase , cytokine , chemistry , immunology , biology , cancer research , biochemistry , in vitro , enzyme
How T‐cells, attracted to local sites of inflammation in arthritides, affect heterotopic ossification is presently unknown. Here, we tested the hypothesis that T‐cell cytokines play a role in the differentiation of human mesenchymal stromal cells (HMSC) into the osteoblast phenotype by inducing autologous BMP‐2, providing a possible mechanism for heterotopic ossification. HMSC from multiple donor bones were treated with either activated T‐cell conditioned medium (ACTTCM) or physiological concentrations of the major inflammatory cytokines, TNF‐α, TGF‐β, IFN‐γ, and IL‐17 (TTII), individually or in combinations. ACTTCM induced BMP‐2 protein in a time‐dependent manner over a 48 h period and alkaline phosphatase (AlkP) within 7 days. In combination, TTII, like ACTTCM, induced AlkP and synergistically induced BMP‐2 protein. Either individually, or in combinations of up to three, the T‐cell cytokines failed to induce BMP‐2 above control levels while a combination of all four cytokines synergistically induced BMP‐2 10‐fold as assessed by ELISA. TTII induced mineralized matrix as effectively as dexamethasone. Inhibition of p38 MAPK completely inhibited TTII‐induced BMP‐2 production and matrix mineralization. Real time RT‐PCR analysis demonstrated a striking early (within 4 h) increase in BMP‐2 gene expression by TTII, which was suppressed by p38 MAP kinase inhibition. In localized chronic inflammatory diseases, T‐cell cytokines released at localized sites of inflammation may be the driving force for differentiation of local mesenchymal stromal cells into the osteoblast phenotype thereby playing a significant role in the heterotopic ossification observed in these diseases. J. Cell. Biochem. 98: 706–714, 2006. © 2006 Wiley‐Liss, Inc.