Enhanced osteoclastogenesis in 4-1BB-deficient mice caused by reduced interleukin-10.
Enhanced osteoclastogenesis was observed in bone marrow-derived macrophage cells from 4-1BB-deficient mice than in those from wildtype mice. 4-1BB and 4-1BB ligand interaction may play a role at a certain stage of osteoclast formation through increased level of IL-10, a negative regulator of osteoclastogenesis.


BACKGROUND
4-1BB is an inducible T-cell costimulatory molecule and a member of the TNF receptor family. The expression pattern of 4-1BB and 4-1BB ligand (4-1BBL) has suggested that 4-1BB plays a role not only in various responses related to innate immunity but also in bone metabolism.


METHODS
Osteoclast formation was evaluated in bone marrow-derived macrophage cells (BMMs) from wildtype and 4-1BB-deficient (4-1BB-/-) mice. Expression of interleukin-10 (IL-10) during osteoclast formation was analyzed at the mRNA and protein levels.


RESULTS
Expression of IL-10 was higher in RANKL-stimulated wildtype BMMs than 4-1BB-/- BMMs. When 4-1BBL was stimulated with 4-1BB-Fc fusion protein, the expression of IL-10 in BMMs increased. Neutralization of IL-10 was not as effective in preventing inhibition by IL-10 of osteoclast differentiation in 4-1BB-/- BMMs as in wildtype BMMs. When IL-10 was added to the culture medium, osteoclast formation was inhibited more efficiently in the 4-1BB-/- BMMs than in the wildtype BMMs.


CONCLUSIONS
Interaction of 4-1BB and 4-1BBL stimulates IL-10 production through 4-1BBL signaling. 4-1BBL plays a role at a certain stage of osteoclast formation, and IL-10 may mediate this effect. The elevated level of osteoclastogenesis in 4-1BB-/- BMMs may thus be caused, in part, by a lower level of IL-10.
Shin
Hyun-Hee
HH
Department of Biological Sciences and the Immunomodulation Research Center, University of Ulsan, Korea.
Lee
Ji-Eun
JE
Lee
Eun A
EA
Kwon
Byoung Se
BS
Choi
Hye-Seon
HS
D053330:4-1BB Ligand / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000172:deficiency / Q000378:metabolism*
D053330:4-1BB Ligand; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D016753:Interleukin-10