Immune cells are thought to play an important role in bone loss caused by inflammation (1, 2). Disabling joint destruction in rheumatoid arthritis and the loss of teeth in periodontal disease are examples of skeletal loss that can occur with inflammation. Resorption of bone by osteoclasts represents the primary mechanism responsible for the loss of bone caused by inflammatory disease.Key factors regulating osteoclastogenesis include macrophage colony-stimulating factor (M-CSF) 2 and receptor activator of nuclear factor-B ligand (RANKL). M-CSF is a secreted product of stromal cells/ osteoblasts that enhances colony expansion of monocyte/osteoclast progenitor cells. RANKL exists both as a transmembrane protein in osteoblasts/stromal cells and as a soluble protein (3-6). RANKL directs the expanded progenitor cell population to the osteoclast lineage by activation of receptor activator of nuclear factor-B (RANK). The interaction between RANKL and RANK can be inhibited by osteoprotegerin (OPG), a decoy receptor released from stromal cells/osteoblasts.RANKL stimulation of RANK causes receptor trimerization and recruitment of tumor necrosis factor receptor-associated factors (TRAFs). TRAF1, 2, 3, and 5 bind to the carboxyl-terminal end of the RANK trimer, whereas TRAF6 binds more closely to the membrane. Downstream intracellular signaling mediated by RANK in osteoclast progenitor cells includes TRAF6-dependent activation of NF-B, mitogen-activated protein kinases (MAP kinases) and AP-1, and activation of c-Src and the phosphatidylinositol 3-kinase/Akt pathway (5-7). In addition, immunoreceptor tyrosine-based activation motif-mediated costimulatory signals have been shown to be required for expression of nuclear factor of activated T-cells 2 (NFAT2), the transcription factor believed to be crucial for osteoclast differentiation (8, 9). Several of these intracellular signaling molecules, including p50/p65, c-Fos, NFAT2, Fc receptor common ␥ subunit (FcR␥)/DNAX-activation protein 12 kD (DAP 12), and TRAF6, as well as RANK, RANKL, OPG, M-CSF, and the M-CSF receptor c-Fms, have been shown by gene deletion studies to be essential for osteoclastogenesis (2, 7, 10 -14).* This work was supported by grants from the Swedish Science Council (project 07525), the Swedish Rheumatism Association, the Royal 80 Year Fund of King Gustav V, the Swedish Dental Society, and the County Council of Västerbotten. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom correspondence should be addressed. Tel.: 46-90-785-6290; Fax: 46-90-139289; E-mail: ulf.lerner@odont.umu.se.2 The abbreviations used are: M-CSF, macrophage colony-stimulating factor; ALP, alkaline phosphatase; ␣-MEM, ␣-modification of minimum essential medium; BMM, bone marrow macrophages; CT, calcitonin; CTR, calcitonin receptor; DAP12, DNAX-activating protein 12; D3, 1,25(OH) 2 -vitamin D 3 ; ERK, e...

IL-1alpha (interleukin-1alpha); IL-1beta (interleukin-1beta); IL-6 (interleukin-6); IL-11 (interleukin-11); LIF (leukemia inhibitory factor); OSM (oncostatin M); alpha(1)-coll. I (alpha(1)-collagen I); ALP (alkaline phosphatase); BMP-2 (bone morphogenetic protein-2); OC (osteocalcin); BSP (bone sialoprotein); TNFR I (tumor necrosis factor receptor I); TNFR II (tumor necrosis factor receptor II); IL-1R1 (interleukin-1 receptor 1); GAPDH (glyceraldehyde-3-phosphate dehydrogenase); RPL13A (ribosomal protein L13A); mRNA (messenger ribonucleic acid); cDNA (complementary deoxyribonucleic acid); PCR (polymerase chain-reaction); BCA (bicinchoninic acid); ELISA (enzyme-linked immunosorbent assay); alpha-MEM (alpha modification of Minimum Essential Medium); and FCS (fetal calf serum).

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The osteotropic interleukin-6 (IL-6) types of cytokines IL-6, IL-11, and leukemia inhibitory factor (LIF), but not oncostatin M, are expressed by human gingival fibroblasts, and their expressions are regulated by IL-1 and tumor necrosis factor-alpha (TNF-alpha). In the present study, we investigated whether signaling through Toll-like receptor 2 (TLR2) can affect the expression of these cytokines in human gingival fibroblasts. Lipopolysac-charide (LPS) from P. gingivalis was found to stimulate IL-6 and LIF mRNA and protein, but not IL-11 or OSM mRNA. Using two synthetic ligands acting specifically at TLR2 and siRNA knockdown of TLR2, we demonstrated the important role of TLR2 in the stimulation of IL-6 and LIF in gingival fibroblasts. Analysis of these data suggests that signaling through the innate immune system controls the expression of osteotropic cytokines in human gingival fibroblasts.

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