Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6.
It has been reported that soluble interleukin (IL)-6 receptor (sIL-6R) is detected in the serum of healthy individuals and its level is increased in patients with multiple myeloma and human immunodeficiency virus infection. Although several reports have suggested that sIL-6R potentiates IL-6 action, its physiological role remains unclear. In this study, we examined the role of sIL-6R on osteoclast formation by IL-6, using a coculture of mouse osteoblasts and bone marrow cells. Neither recombinant mouse IL-6 (mIL-6) nor mouse sIL-6R (smIL-6R) induced osteoclast-like multinucleated cell (MNC) formation when they were added separately. In contrast, simultaneous treatment with mIL-6 and smIL-6R strikingly induced MNC formation. These MNCs satisfied major criteria of authentic osteoclasts, such as tartrate-resistant acid phosphatase (TRAP) activity, calcitonin receptors, and pit formation on dentine slices. The MNC formation induced by mIL-6 and smIL-6R was dose-dependently inhibited by adding monoclonal anti-mouse IL-6R antibody (MR16-1). It is likely that osteoblasts and osteoclast progenitors are capable of transducing a signal from a complex of IL-6 and sIL-6R through gp130, even though they may have no or a very small number of IL-6Rs. Factors such as IL-11, oncostatin M, and leukemia inhibitory factor, which are known to exert their functions through gp130 (the signal-transducing chain of IL-6R), also induced MNC formation in our coculture system. These results suggest that increased circulating or locally produced sIL-6R induces osteoclast formation in the presence of IL-6 mediated by a mechanism involving gp130. This may play an important physiological or pathological role in conditions associated with increased osteoclastic bone resorption.
Tamura
T
T
Department of Biochemistry, School of Dentistry, Showa University, Tokyo, Japan.
Udagawa
N
N
Takahashi
N
N
Miyaura
C
C
Tanaka
S
S
Yamada
Y
Y
Koishihara
Y
Y
Ohsugi
Y
Y
Kumaki
K
K
Taga
T
T
D000818:Animals; D000911:Antibodies, Monoclonal; D001854:Bone Marrow Cells; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000097:blood / Q000276:immunology; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018123:Receptors, Interleukin / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins