Recombinant interleukin-1 stimulates prostaglandin E2 production by osteoblastic cells: Synergy with parathyroid hormone (original) (raw)
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Role of prostaglandins in interleukin-1-induced bone resorption in mice in vitro
Journal of Bone and Mineral Research, 2009
The mechanism of bone resorption induced by interleukin 1 (IL-1) was examined in mice using three different in vitro assay systems: a fetal long bone organ culture system, a bone marrow culture system, and a coculture system of primary osteoblastic cell populations and spleen cells. In the organ culture system, recombinant human IL-la (rhIL-la) increased both bone resorption and osteoclast number. Both were partially suppressed in the presence of indomethacin. In the marrow culture, both rhIL-la and rhIL-10 stimulated osteoclastlike cell formation, which was completely inhibited by adding indomethacin concurrently. Furthermore, there was a good correlation between the number of osteoclastlike cells formed and the amount of prostaglandin E, (PGE,) released into the culture media. This indicates that PGE, is involved in the mechanism of IL-1-mediated osteoclastlike cell formation. In the coculture of primary osteoblastic cell populations and spleen cells, rhIL-1 again stimulated osteoclastlike cell formation, which was inhibited by adding indomethacin. In the cocultures in which direct interaction between osteoblastic cells and spleen cells was inhibited, PGE, synthesis was similarly increased but no osteoclastlike cells were formed. These results indicate that IL-1 induces osteoclast formation by a mechanism involving PG (most likely PGE,). Furthermore, direct interaction between osteoclast progenitors and osteoblastic cells is required in the osteoclast recruitment induced by IL-1.
Cytokine, 1991
(IL-lp) caused a dose-and time-dependent enhancement of the release of 45Ca from prelabeled mouse calvaria in organ culture. In addition, IL-D3 dose-dependently stimulated the formation of prostaglandin E, (PGE,) and 6-keto-PGF,, in the calvarial bones. However, IL-lp-induced 45Ca release was only partially inhibited by blocking the PGEz response with indomethacin, suggesting that enhanced PGE, formation in response to IL-lp is not necessary to obtain a bone resorptive effect, but that prostaglandins potentiate the action of IL-@. The synthetic nonapeptide VQGEESNDK, corresponding to the fragment 163-171 of human IL-ll3, administered simultaneously with antigen (SRBC) to C3H/HeN male mice, induced a dose-dependent enhancement of specific antibody-producing cells in the spleen (PFC). The degree of PFC stimulation was comparable to that caused by native human IL-& In mouse bone cultures, neither 4sCa release nor prostanoid formation was stimulated by fragment 163-171. These data indicate that (1) IL-lp-induced stimulation of bone resorption is dissociable from IL-lfi-induced increase of prostanoid biosynthesis and (2) the epitope of the IL-ll3 molecule involved in the immunostimulatory effects may be different from that involved in the stimulatory effects on bone resorption.
IL-1 plays an important role in the bone metabolism under physiological conditions
International Immunology, 2010
It is well known that IL-1 is involved in bone resorption under pathological conditions. The role of this cytokine in bone remodeling under physiological conditions, however, remains obscure. In this study, we addressed the role of IL-1 in physiological bone metabolism through analyses of IL-1adeficient (KO), IL-1b KO and IL-1a/b double KO mice that were housed under specific pathogen free conditions. The femur mineral density, trabecular bone mass and cortical thickness significantly increased in all KO mice compared with wild-type (WT) mice. The number of osteoclasts in trabecular bones decreased, suggesting that IL-1 regulates bone metabolism through regulation of osteoclast formation. When differentiation of bone marrow (BM) cells into osteoclasts was induced by parathyroid hormone in co-cultures of osteoblasts and BM cells from WT and IL-1a/b KO mice, IL-1a/b KO BM cell co-cultures failed to undergo efficient osteoclast-like multinucleated cell (OCL) differentiation, although high levels of receptor activator of nuclear factor-kB (NF-kB) ligand (RANKL) was induced. In contrast, efficient OCL differentiation was observed in IL-1a/b KO osteoblast/WT BM cell co-cultures, in which high levels of IL-1a/b and low levels of RANKL were produced. Addition of IL-1a to IL-1a/b KO BM-derived macrophage cultures markedly enhanced OCL differentiation induced by soluble RANKL, and the downstream molecules of receptor activator of NF-kB (RANK) including c-Jun N-terminal factor, extracellular signal-regulated kinase and c-Fos were less activated in the absence of IL-1 upon treatment with RANKL. Taken together, these results indicate that IL-1 directly activates RANK signaling other than inducing RANKL to promote osteoclastogenesis and plays an important role in physiological bone metabolism.
The Journal of Immunology, 2005
Bone loss is a typical pathological feature of chronic inflammatory bone diseases including rheumatoid arthritis, in which CD4 effector T cells play critical roles. We found that activated mouse Th2 and not Th1 cells produced the parathyroid hormone (PTH). Unlike in the parathyroid cells, PTH expression in Th2 cells was not regulated by the fluctuation of calcium level, but rather it required the full activation of the T cells. Although PTH was expressed in immature Th2 cells, and its receptor was transiently expressed during Th1 and Th2 cell differentiation, PTH did not significantly affect the outcome of the differentiation. In primary osteoblasts cultured in Th2 cell condition medium, the alkaline phosphatase (ALP) activity was maintained at a basal level. However, antagonizing PTH in the condition medium resulted in a significant reduction of the ALP activity. These results demonstrated an important role of the Th2 cell-derived PTH in maintaining the bone-forming activity of the osteoblasts under inflammatory conditions. In osteoblasts cultured in the Th1 cell condition medium, the ALP activity was significantly suppressed. Neutralizing IFN-␥ alleviated the suppression. Conversely, treatment of osteoblasts with IFN-␥ suppressed the ALP activity. Unlike ALP, expression of the major bone matrix proteins by the osteoblasts was only minimally affected by either Th1 or Th2 cytokine environment. In addition, the Th2 cytokine environment also regulated to expression of receptor activator of NF-B ligand and osteoprotegerin through both PTH-dependent and-independent mechanisms. Our study therefore identified new regulatory events in bone remodeling under inflammatory conditions.
Archives of Oral Biology, 1990
Cultured human periodontal ligament fibroblasts showed synergistic elevations in the synthesis of prostaglartdin E and production of CAMP by the administration of parathyroid hormone and cytokines (interleukin-la, -lb, or tumour necrosis factor-a). Unstimulated conditioned media derived from these fibroblasts contained bone-resorbing activity. In addition, conditioned media generated by cytokine-or parathyroid hormone-treated fibroblasts showed further increases in bone-resorbing activity. The effects were additive when the hormone was combined with either one of the cytokines in stimulating bone resorption. These findings suggest that the effect of parathyroid hormones and cytokines together on bone resorption can be mediated in part by human periodontal ligament fibroblasts via PGE production and subsequent PGE action on the osteoclasts.
Biochemical and Biophysical Research Communications, 1989
Osteogenic cells mediate PTH-stimulated osteoclastic bone resorption by a yet unidentified mechanism. We show that primairy rat osteoblast-like cells and the clonal osteogenic sarcoma cell line UMR-106 produce interleukin-6 (IL-6) and that bPTH(l-84) and synthetic hPLP(l-34) stimulate this production dose-dependently. With both peptides a close relation between IL-6 and cyclic-AMP production was found, though for PTH concentrations higher than 2.10-e M a clear dissociation was observed. Significant IL-6 activity was also detected in media of cuttures of1 jr-day-old fetal mouse radii and metacarpals which was clearly stimulated by PTH. The source of IL-6 in these bone explants seems to be the osteogenic (cartilage) cells. Treatment of bone explants with IL-6 induced osteoclastic resorption which, however, depended on the bone resorption system used. This bone resorbing action of IL-6 is exerted probably through an effect on the formation of osteoclasts (osteoclastogenesis) rather than on the activation of already existing mature osteoclasts. We suggest that IL-6 produced by osteogenic cells may be a mediator in PTH-stimulated osteoclastic bone resorption.
FEBS Letters, 1984
Local production of prostaglandins by osteoblasts may be important in controlling the bone resorbing activity of some hormones which have receptors on osteoblasts. We have demonstrated that osteoblast-like cells derived from human bone can incorporate [14C]arachidonic acid into phospholipids and synthesise immunoreactive PGE. Parathyroid hormone increases both the release of incorporated arachidonic acid and the synthesis of PGE. This is the first demonstration of modulation of bone cell prostaglandin synthesis by a bone resorbing hormone. Human bone cell Prostaglandin PTH 1,2SDihydroxyvitamin D3 2.2. Measurement of prostaglandins Cells were passaged using 0.5% trypsin/0.02% EDTA into 3.5 or 1.6 cm multiwells at varying cell densities (fig.1) and allowed to settle for 24 h.
Journal of the American Society of Nephrology, 1999
The N-terminal region of both parathyroid hormone (PTH) and PTH-related protein (PTHrP) binds to the same PTH/PTHrP receptor in osteoblasts. However, C-terminal PTHrP (107-139) inhibits growth and various functions of osteoblasts and osteoclasts apparently through PTHrP-specific receptors. PTH (1-34) and PTHrP (1-34) rapidly induce interleukin-6 (IL-6) expression by osteoblasts. The aim of the present study was to assess the effects of PTHrP (107-139) on IL-6 gene expression and secretion by osteoblastic cells from human trabecular bone (hOB). Using reverse transcription followed by PCR, it was found that IL-6 mRNA was twofold maximally increased by either PTHrP (1-34) or PTHrP (107-139), at 10 nM, over basal within 1 to 2 h in hOB cells. This effect of PTHrP (107-139), and that of PTHrP (1-34), were abolished by the transcription inhibitor actinomycin D. Meanwhile, puromycin, a protein synthesis inhibitor, superinduced IL-6 expression in the presence or absence of each PTHrP peptide. Both PTHrP (1-34) and PTHrP (107-139), but not PTHrP (38-64), stimulated IL-6 secretion to the hOB cellconditioned medium at 24 h, dose dependently. In addition, this maximal stimulatory effect (twofold over basal) was similar with each PTHrP peptide alone, and not additive when added together. PTHrP (107-139) stimulation of mRNA and protein in hOB cells was abolished by bisindolylmaleimide I, a protein kinase C inhibitor, but not by either adenosine 3Ј,5Јcyclic monophosphorothioate, Rp-isomer (Rp-cAMPS), or N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89), two protein kinase A inhibitors. These results indicate that C-terminal PTHrP, like its N-terminal domain, induces IL-6 production by human osteoblastic cells. This effect of both PTHrP regions could provide a mechanism to modulate bone turnover.
Endocrinology, 2013
Glucocorticoid (GC) excess causes a rapid loss of bone with a reduction in bone formation. Intermittent PTH (1-34) administration stimulates bone formation and counteracts the inhibition of bone formation by GC excess. We have previously demonstrated that mechanical strain enhances interleukin (IL)-11 gene transcription by a rapid induction of ΔFosB expression and protein kinase C (PKC)-δ-mediated phosphorylation of phosphorylated mothers against decapentaplegic (Smad)-1. Because IL-11 suppresses the expression of dickkopf-1 and -2 and stimulates Wnt signaling, IL-11 appears to mediate at least a part of the effect of mechanical strain on osteoblast differentiation and bone formation. The present study was undertaken to examine the effect of PTH(1-34) and GCs on IL-11 expression in murine primary osteoblasts (mPOBs). PTH(1-34) treatment of mPOBs enhanced IL-11 expression in a time- and dose-dependent manner. PTH(1-34) also stimulated ΔFosB expression and Smad1 phosphorylation, which...
Interleukin-6 is produced by bone and modulated by parathyroid hormone
Journal of Bone and Mineral Research, 2009
Interleukind (IL-6) is a cellular regulatory molecule, the diverse functions of which relate to cells both within and outside the immune system. In this report we demonstrated that bone tissue, specifically osteoblasts, produce interleukin-6 and that this function can be modulated by the osteotrophic hormone parathyroid hormone (PTH). Given that the complex process of bone remodeling is now thought to be regulated not only by systemic hormones but also by locally produced factors, the existence of a parathyroid hormone-stimulated production of interleukin-6 by osteoblasts may have important physiological significance.