Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors.
BACKGROUND
The interaction between the immune and skeletal systems is evidenced by the bone loss observed in autoimmune diseases such as rheumatoid arthritis. In this paper we describe a new mechanism by which the immune cytokine IL-17A directly affects osteoclastogenesis.


METHODS
Human CD14+ cells were isolated from healthy donors, cultured on dentine slices and coverslips and stimulated with IL-17A and/or receptor activator of NF-kappaB ligand (RANKL). Osteoclast differentiation was evaluated by gene expression, flow cytometry, tartrate-resistant acid phosphatase staining, fluorescence and electron microscopy. Physiologic bone remodelling was studied in wild-type (Wt) and IL-17A-/- mice using micro-computer tomography and serum RANKL/osteoprotegerin concentration. Functional osteoclastogenesis assays were performed using bone marrow macrophages isolated from IL-17A-/- and Wt mice.


RESULTS
IL-17A upregulates the receptor activator for NF-kappaB receptor on human osteoclast precursors in vitro, leading to increased sensitivity to RANKL signalling, osteoclast differentiation and bone loss. IL-17A-/- mice have physiological bone homeostasis indistinguishable from Wt mice, and bone marrow macrophages isolated from these mice develop fully functional normal osteoclasts.


CONCLUSIONS
Collectively our data demonstrate anti-IL-17A treatment as a selective therapeutic target for bone loss associated with autoimmune diseases.
Adamopoulos
Iannis E
IE
Discovery Research, Schering-Plough Biopharma (formerly DNAX Research, Inc,), 901 South California Avenue, Palo Alto, CA 94304, USA. iannis.adamopoulos@spcorp.com
Chao
Cheng-Chi
CC
Geissler
Richard
R
Laface
Drake
D
Blumenschein
Wendy
W
Iwakura
Yoichiro
Y
McClanahan
Terrill
T
Bowman
Edward P
EP
D000818:Animals; D016723:Bone Remodeling / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002469:Cell Separation; D002478:Cells, Cultured; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D053245:RANK Ligand / Q000096:biosynthesis*; D013234:Stem Cells / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D015854:Up-Regulation
D020381:Interleukin-17; D053245:RANK Ligand; C505688:TNFSF11 protein, human