JOURNAL OF BONE A N D MINERAL RESEARCH Volume 6, Number 10, 1991 Mary Ann Liebert, Inc., Publishers

Letter to the Editor The Bone-Resorbing Activity of Interleukin-6 resorb much more extensively if PGE generation has not been inhibited during the preincubation period.'51 In the Recently, Al-Humidan et al.Il1 reported in the Journal same context, a strong synergy between IL-1 and IL-6 is of Bone and Mineral Research that human interleukin-6 observed whereas the bone-resorbing effects of IL-I are (IL-6) does not stimulate bone resorption in neonatal partly inhibited by an anti-IL-6 antibody (thus showing the mouse calvariae. They therefore concluded that IL-6 was bone effects of IL-I to be mainly mediated by 11-6).(b) "unlikely to be involved in the resorption that occurs in pa- Thus, it is clear that the nature of the osteoclasts and tients with myeloma or around rheumatoid joints."") A osteoclast precursors present in the organ cultures influfew months ago, Ishimi et al.(z)published in the Journal ences IL-6 responsiveness (Table 1). In humans, it has reof Immunology that 1L-6 was produced by osteoblasts and cently been shown that IL-6 stimulated rather early osteoinduced bone resorption in fetal mouse calvariae. They clast precursor^.(^^^^ It is also clear that endogenous PGEs concluded that their data indicated that "IL-6 might be in- are critical. Another point that could be critical is the presvolved in bone resorption in patients with active rheuma- ence of variable amounts of endogenous IL-6 in these diftoid arthritis (RA) and multiple myeloma (MM) as ferent organ cultures.(l) Such endogenous production of well."(z1 How can we reconcile these apparently opposite IL-6 could be largely influenced by endogenous PGEs data, considering that, as emphasized by both Al-Humi- themselves (Aarden, oral communication, Lyon, France, dan and Ishimi, the bone biology of IL-6 could be highly September 1990). The reference to PGEs is essential since relevant to that of rheumatoid arthritis and multiple both synovial fluids from patients with RA and bone marmyeloma? row samples from those with MM contain high amounts The most simple answer is that the different methodolo- (ng/ml) of PGEs (in association with high amounts of gies used in these studies explain the opposite results. In- IL-6). deed, Al-Humidan et aI.[l1 worked with neonatal mouse In conclusion, we think that the respective works of Alcalvariae and addded indomethacin during the 24 h prein- Humidan et al.(I) and Ishimi et al.") are not in conflict. As cubation period, as recommended by Lerner.I3) On the presented in this letter, these works should be reappraised other hand, Ishimi et al.") worked with fetal mouse cal- in terms of target cells for IL-6 in these organ cultures and, variae and did not neutralize the endogenous synthesis of above all, in terms of the presence (or not) of endogenous prostaglandins of the E series (PGEs) with indomethacin PGEs. As emphasized here, this latter point is critical to during the 24 h preincubation period. Such a difference in understand the pathogenesis of RA and MM-induced bone the methodology is probably critical. First, the osteoblastic changes. Finally, the bone-resorbing activity of IL-6 in and osteoclastic environments are probably different in vivo is supported directly by IL-6-induced hypercalcemia neonatal and fetal mouse calvariae. Such differences could in mouse[b1and indirectly by the hypocalcemic effects of explain differences in terms of IL-6 responsiveness. This anti-IL-6 treatment in patients with MM and hypercalpossibility is supported by recent data from Lowik et al.,(4) ~ e m i a . ' ~ ) showing that IL-6 had no effect at all on the resorption of fetal mouse radii (containing mature osteoclasts) but stimulated the bone resorption of metacarpals (containing only osteoclast precursors in the periosteum). Second, blocking TABLE 1. BONE-RESORBING ACTIVITY OF INTERLEUKIN-6 or not blocking the endogenous synthesis of PGEs by indomethacin during the preincubation period is also proba- Detectable Undetectable bly of critical importance (discussed in Ref. 3). Indeed, metacarpal^'^^ Fetal long Garrett and Mundy showed that after a preculture period of 24 h in control media, osteoclast numbers and resorp- Fetal mouse calvariae(z) Neonatal mouse calvariae'l a tion areas are markedly enhanced in neonatal ~ a l v a r i a e . ' ~ ) a Although exogenous IL-6 alone has no bone-resorbing activity This increase in osteoclast formation was inhibited by the in this organ culture system, endogenous IL-6 mediates the effects addition of indomethacin during the preincubation period. of 1L-1 and tumor necrosis factor (TNF) and exogenous IL-6 amAdding PGEs could reverse the inhibitory effect of indo- plifies the effects of IL-1 and TNF.'"' methacin.") These data were in complete agreement with those previously published by Lerner, showing that this Regis Bataille, M.D., Ph.D., and Bernard Klein, Ph.D. PGE-induced generation of osteoclasts later influenced re- INSERM U 291, Immunopathology sorptive responses to exogenous factors.(31For example, 99, rue Puech-Villa, Zolad when IL-1 is added to neonatal mouse calvariae, the bones 34100 Montpellier Cedex, France

To the Editor:





REFERENCES 1. Al-Humidan A, Ralston SH, Hughes DE, Chapman K,





Aarden L, Russell RGG, Gowen M 1991 Interleukin-6 does not stimulate bone resorption in neonatal mouse calvaria. J Bone Miner Res 6:3-8. lshimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, Yamaguchi A, Yoshiri S , Matsuda T, Hirano T, Kishimoto T, Suda T 1990 IL-6 is produced by osteoblasts and induces bone resorption. J lmmunol 1493297-3303. Lerner UH 1987 Modifications of the mouse calvaria technique improve the responsiveness to stimulators of bone resorption. J Bone Miner Res 2:375-383. Lowik C, Van Der Pluijm 0, Hoekman K, Aarden L, Bijvoet 0, Papapoulos S 1989 IL-6 produced by PTH-stimulated osteogenic cells can be a mediator in osteoclast recruitment. J Bone Miner Res 4(Suppl. 1):S257. Garrett IR, Mundy GR 1989 Relationship between interleu-





kin-1 and prostaglandins in resorbing neonatal calvaria. J Bone Miner Res 4:789-794. Black KS, Mundy GR, Garrett IR 1990 Interleukin-6 causes hypercalcemia in vivo and enhances the bone resorbing potency of interleukin-l and tumor necrosis factor by two orders of magnitude in vitro. J Bone Miner Res S(Suppl. 2):787. Kurihara N , Bertolini D, Suda T, Akiyama Y, Roodman GD 1990 Interleukin-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-I release. J Immunol 144:4226-4230. Kurihara N, Civin C, Roodman GD 1991 Osteotropic factor responsiveness of highly purified population of early and late precursors for human multinucleated cells expressing the osteoclast phenotype. J Bone Miner Res 6:257-261. Klein B, Wijdenes T, Jourdan M, Boiron JM, Sany J, Bataille R 1990 Monoclonal anti-lL-6 antibodies block myeloma cell proliferation in vivo. Blood 76(Suppl. 1): 1418.

The bone-resorbing activity of interleukin-6.

JOURNAL OF BONE A N D MINERAL RESEARCH Volume 6, Number 10, 1991 Mary Ann Liebert, Inc., Publishers Letter to the Editor The Bone-Resorbing Activity...
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