The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures.
Interleukin (IL)-11 is a multifunctional cytokine whose role in osteoclast development has not been fully elucidated. We examined IL-11 production by primary osteoblasts and the effects of rat monoclonal anti-mouse glycoprotein 130 (gp130) antibody on osteoclast formation, using a coculture of mouse osteoblasts and bone marrow cells. IL-1, TNF alpha, PGE2, parathyroid hormone (PTH) and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) similarly induced production of IL-11 by osteoblasts, but IL-6, IL-4, and TGF beta did not. Primary osteoblasts constitutively expressed mRNAs for both IL-11 receptor (IL-11R alpha) and gp130. Osteotropic factors did not modulate IL-11R alpha mRNA at 24 h, but steady-state gp130 mRNA expression in osteoblasts was upregulated by 1 alpha,25(OH)2D3, PTH, or IL-1. In cocultures, the formation of multinucleated osteoclast-like cells (OCLs) in response to IL-11, or IL-6 together with its soluble IL-6 receptor was dose-dependently inhibited by rat monoclonal anti-mouse gp130 antibody. Furthermore, adding anti-gp130 antibody abolished OCL formation induced by IL-1, and partially inhibited OCL formation induced by PGE2, PTH, or 1 alpha,25(OH)2D3. During osteoclast formation in marrow cultures, a sequential relationship existed between the expression of calcitonin receptor mRNA and IL-11R alpha mRNA. Osteoblasts as well as OCLs expressed transcripts for IL-11R alpha, as indicated by RT-PCR analysis and in situ hybridization. These results suggest a central role of gp130-coupled cytokines, especially IL-11, in osteoclast development. Since osteoblasts and mature osteoclasts expressed IL-11R alpha mRNA, both bone-forming and bone-resorbing cells are potential targets of IL-11.
Romas
E
E
St. Vincent's Institute of Medical Research, University of Melbourne, Victoria, Australia.
Udagawa
N
N
Zhou
H
H
Tamura
T
T
Saito
M
M
Taga
T
T
Hilton
D J
DJ
Suda
T
T
Ng
K W
KW
Martin
T J
TJ
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D001483:Base Sequence; D001853:Bone Marrow / Q000276:immunology*; D001854:Bone Marrow Cells; D002117:Calcitriol / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000494:pharmacology*; D017931:DNA Primers; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000494:pharmacology; D017370:Interleukin-11 / Q000096:biosynthesis*; D053703:Interleukin-11 Receptor alpha Subunit; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D010281:Parathyroid Hormone / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018123:Receptors, Interleukin / Q000378:metabolism*; D053702:Receptors, Interleukin-11; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016207:Cytokines; D017931:DNA Primers; C508428:IL11RA protein, human; C494199:IL6ST protein, human; C508429:Il11ra1 protein, mouse; C508430:Il11ra1 protein, rat; C508431:Il11ra2 protein, mouse; C494200:Il6st protein, mouse; C494201:Il6st protein, rat; D007375:Interleukin-1; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D050822:Cytokine Receptor gp130; D002117:Calcitriol; D015232:Dinoprostone