Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors.
We reported that interleukin (IL) 6 alone cannot induce osteoclast formation in cocultures of mouse bone marrow and osteoblastic cells, but soluble IL-6 receptor (IL-6R) strikingly triggered osteoclast formation induced by IL-6. In this study, we examined the mechanism of osteoclast formation by IL-6 and related cytokines through the interaction between osteoblastic cells and osteoclast progenitors. When dexamethasone was added to the cocultures, IL-6 could stimulate osteoclast formation without the help of soluble IL-6R. Osteoblastic cells expressed a very low level of IL-6R mRNA, whereas fresh mouse spleen and bone marrow cells, both of which are considered to be osteoclast progenitors, constitutively expressed relatively high levels of IL-6R mRNA. Treatment of osteoblastic cells with dexamethasone induced a marked increase in the expression of IL-6R mRNA. By immunoblotting with antiphosphotyrosine antibody, IL-6 did not tyrosine-phosphorylate a protein with a molecular mass of 130 kD in osteoblastic cells but did so in dexamethasone-pretreated osteoblastic cells. Osteoblastic cells from transgenic mice constitutively expressing human IL-6R could support osteoclast development in the presence of human IL-6 alone in cocultures with normal spleen cells. In contrast, osteoclast progenitors in spleen cells from transgenic mice overexpressing human IL-6R were not able to differentiate into osteoclasts in response to IL-6 in cocultures with normal osteoblastic cells. These results clearly indicate that the ability of IL-6 to induce osteoclast differentiation depends on signal transduction mediated by IL-6R expressed on osteoblastic cells but not on osteoclast progenitors.
Udagawa
N
N
Department of Biochemistry, School of Dentistry, Showa University, Tokyo, Japan.
Takahashi
N
N
Katagiri
T
T
Tamura
T
T
Wada
S
S
Findlay
D M
DM
Martin
T J
TJ
Hirota
H
H
Taga
T
T
Kishimoto
T
T
Suda
T
T
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D012886:Skull / Q000166:cytology; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
D015703:Antigens, CD; D015850:Interleukin-6; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases