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And Α Mediated in Part by Enhanced IL-1 Formation in Spleen-Ost 1,25 (OH)2 Vitamin D3-Stimulated Osteoclast Formation in Spleen-Osteoblast Cocultures Is Mediated in Part by Enhanced IL-1α and Receptor Activator of NF- κB Ligand This information is current as Production in Osteoblasts of September 28, 2021. Sun-Kyeong Lee, Judy Kalinowski, Sandra Jastrzebski and Joseph A. Lorenzo J Immunol 2002; 169:2374-2380; ; doi: 10.4049/jimmunol.169.5.2374 Downloaded from http://www.jimmunol.org/content/169/5/2374 References This article cites 58 articles, 9 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/169/5/2374.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology 1,25 (OH)2 Vitamin D3-Stimulated Osteoclast Formation in Spleen-Osteoblast Cocultures Is Mediated in Part by Enhanced IL-1␣ and Receptor Activator of NF-␬B Ligand Production in Osteoblasts1 Sun-Kyeong Lee,2 Judy Kalinowski, Sandra Jastrzebski, and Joseph A. Lorenzo We examined the ability of 1,25 (OH)2 vitamin D3 (Vit D) to stimulate osteoclast-like cell (OCL) formation in cocultures of spleen cells and primary calvarial osteoblasts from wild-type (WT) and IL-1R type 1-deficient (knockout; KO) mice. Vit D dose depen- dently increased OCL in cocultures containing WT osteoblasts. In contrast, there was a 90% reduction in OCL numbers in cocultures containing KO osteoblasts. In cocultures with either WT or KO osteoblasts, treatment with Vit D increased receptor Downloaded from activator of NF-␬B ligand mRNA by 17-, 19-, or 3.5-fold, respectively. Vit D decreased osteoprotegerin mRNA to undetectable in all groups. Intracellular IL-1␣ protein increased after Vit D treatment in cocultures containing WT, but not KO osteoblasts. We also examined direct effects of Vit D, IL-1␣, and their combination on gene expression in primary osteoblasts. In WT cells, Vit D and IL-1 stimulated receptor activator of NF-␬B ligand mRNA expression by 3- and 4-fold, respectively, and their combination produced a 7-fold increase. Inhibition of osteoprotegerin mRNA in WT cells was partial with either agent alone and greatest with ␣ their combination. In KO cells, only Vit D stimulated a response. IL-1 alone increased IL-1 protein expression in WT osteoblasts. http://www.jimmunol.org/ However, in combination with Vit D, there was a synergistic response (100-fold increase). In KO cultures, there were no effects of IL-1, Vit D, or their combination on IL-1␣ protein. These results demonstrate interactions between IL-1 and Vit D in primary osteoblasts that appear important in both regulation of IL-1␣ production and the ability of Vit D to support osteoclastogenesis. The Journal of Immunology, 2002, 169: 2374–2380. nterleukin-1 is a proinflammatory cytokine that is a potent been described (9). IL-1R1 binds both IL-1␣ and ␤ and appears to stimulator of bone resorption and inhibitor of bone formation be the principal mediator of IL-1 actions. The type 2 IL-1R (IL- (1). A variety of cells in the bone microenvironment, includ- 1R2) has a short cytoplasmic tail and does not transmit a biologic I by guest on September 28, 2021 ing monocyte/macrophages, osteoblasts, and osteoclasts, can syn- signal. Instead, it is believed to be a decoy receptor, which binds thesize IL-1 (2). Production of IL-1 has been linked to the disease IL-1␣ and ␤ to prevent their binding to IL-1R1. Estrogen can osteoporosis because inhibitors of IL-1 activity block the bone loss regulate IL-1R1 and IL-1R2 on osteoclasts, and this response may in mice that occurs with ovariectomy (3). In addition, mice, which be involved in the effects that estrogen has on bone (10). Binding are insensitive to IL-1 because they lack the bioactive type 1 IL-1R of IL-1 to cells requires interaction between the IL-1R accessory (IL-1R1),3 fail to lose bone mass after ovariectomy (4). In humans, protein and IL-1R1 or IL-1R2 (11). the presence of osteoporotic fractures was linked to a polymor- Osteoclasts form in vitro through the interactions of hemopoi- phism in the gene locus for IL-1R antagonist (IL-1Ra) in two stud- etic cells, which contain osteoclast precursors, and support cells of ies (5, 6), but not in a third (7). mesenchymal origin (stromal cells or osteoblasts; Ref. 12). The Two biologically active isoforms of IL-1 are known. IL-1␣ and latter produce factors that are required for the maturation and ter- IL-1␤ have similar biologic activities and structure and both bind minal differentiation of osteoclast precursor cells. It appears that the same receptors. A third IL-1 isoform, IL-1Ra, is a competitive physical interactions between osteoclast precursor cells and mes- inhibitor of IL-1␣ and ␤. It binds the bioactive IL-1R1 without enchymal support cells are necessary for osteoclasts to form in stimulating downstream events (8). Two receptors for IL-1 have response to signals from most resorption stimuli (13). Among the cytokines that are produced by mesenchymal sup- port cells and have been identified as regulating osteoclast devel- Division of Endocrinology, Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030 opment are receptor activator of NF-␬B ligand (RANKL) and os- Received for publication October 11, 2001. Accepted for publication June 24, 2002. teoprotegerin (OPG; Ref. 12). RANKL is a TNF-like protein, The costs of publication of this article were defrayed in part by the payment of page which binds to a receptor on osteoclast precursor cells, named charges. This article must therefore be hereby marked advertisement in accordance receptor activator of NF-␬B (RANK). OPG is a soluble decoy with 18 U.S.C. Section 1734 solely to indicate this fact. receptor for RANKL that is released from cells, binds RANKL, 1 This work was supported by Grant PO1-AR38933 from the U.S. Public Health and prevents it from interacting with RANK. Stimulators of re- Service. sorption enhance RANKL production in mesenchymal support 2 Address correspondence and reprint requests to Dr. Sun-Kyeong Lee, Division of Endocrinology, University of Connecticut Health Center, AM047, MC 1850, 263 cells, and some also inhibit OPG (14, 15). Regulation of RANKL Farmington Avenue, Farmington, CT 06030. E-mail address: [email protected] and OPG in bone is believed to be a critical mechanism for the 3 Abbreviations used in this paper: IL-1R1, type 1 IL-1R; OCL, osteoclast-like cell; precise management of osteoclastogenesis and bone resorption. WT, wild type; KO, knockout; OPG, osteoprotegerin; IL-1Ra, IL-1R antagonist; IL- In the current study, we examined the role of IL-1 in the osteo- 1R2, type 2 IL-1R; HIFBS, heat-inactivated FBS; TRAP, tartrate-resistant acid phos- phatase; PBM, peripheral monocyte; RANK, receptor activator of NF-␬B; RANKL, clastogenic response to 1,25 (OH)2 vitamin D3 (Vit D) by exam- RANK ligand; Vit D, 1,25 (OH)2 vitamin D3. ining the effects that Vit D had on cocultures of spleen cells, which Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 The Journal of Immunology 2375 are primarily hemopoietic in origin, and primary murine osteo- PCR amplification was done as previously described (19) using gene- blasts, which derive from mesenchymal cells. In these cultures specific primers and Taq polymerase (AmpliTaq; Applied Biosystems, either, both, or neither the hemopoietic and mesenchymal cells Norwalk, CT). The PCR mixture (without enzyme) was overlaid with min- eral oil and heated to 94°C for 5 min. During the last minute, AmpliTaq were from wild-type (WT) or IL-1R1-deficient mice. was added (hot start) and amplification was allowed to proceed in a thermal cycler (Applied Biosystems). Temperature cycling was as follows: dena- Materials and Methods turation at 94°C for 1 min, primer annealing at 65°C for 2 min, and ex- Mice tension at 72°C for 3 min for 10 cycles. In subsequent cycles, the primer annealing temperature was decreased stepwise (step-down method) by 5°C IL-1R1-deficient (knockout; KO) mice were a gift from Dr. J. Peschon every five cycles. After the last cycle, the mixture was incubated at 72°C (Immunex, Seattle, WA; Refs. 4 and 16). Animals were in a mixed C57BL/ for 7 min. To verify that amplification was in the linear range for each PCR 6 ϫ 129Sv background. WT controls were also C57BL/6 ϫ 129Sv mice analysis, we performed PCR amplification between 24 and 36 cycles at that were derived from the same heterozygous breeding pair, which have three cycle intervals, and measured product yield as previously described been used to generate the homozygous KO mice. (19). Specific amplimer sets are designed from published cDNA sequences: murine RANKL (27) spanning all five exons (antisense: 5Ј-TCCCGAT Materials GTTTCATGATGC-3Ј, sense: 5Ј-TGTACTTTCGAGCGCAGATG-3Ј), Ј Recombinant human IL-1␣ and IL-1Ra were from R&D Systems (Minne- murine OPG (28) spanning exons II to V (antisense: 5 -TCAAGTGCTT Ј Ј Ј apolis, MN) and ELISA kits for murine IL-1␣ was from Endogen GAGGGCATAC-3 ; sense: 5 -TGGAGATCGAATTCTGCTTG-3 ), mu- ␤ Ј Ј (Woburn, MA).
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