Prime role of bone IL-1 in mice may lie in emergency Ca(2+)-supply to soft tissues, not in bone-remodeling.
IL-1 and TNF-α are thought to be important bone-remodeling regulators. However, mice lacking either them or their receptors reportedly grow healthily. Here, we examined the roles of IL-1 and TNF-α in bone. Although a significant IL-1 level was detected in the tibia of non-stimulated wild-type (WT) mice, no significant physicochemical, morphological, or histological defects were detected in the tibias in mice lacking IL-1 (both α and β types) (IL-1KO) or lacking both IL-1 and TNF-α (IL-1/TNF-αKO). Injection of sub-lethal doses of lipopolysaccharide (LPS) into WT mice induced a transient hypocalcemia, increased IL-1 (in the plasma and markedly in the tibia), and increased TNF-α (markedly in the plasma, but only slightly in the tibia). LPS-induced hypocalcemia was modest in IL-1KO mice, and not detected in IL-1/TNFαKO mice. IL-1α (but not TNFα) induced hypocalcemia in both WT and IL-1KO mice. In both WT and IL-1KO mice treated with clodronate (osteoclast inhibitor), the LPS-induced hypocalcemia was markedly augmented. Nifedipine (inhibitor of both voltage-activated and capacitative Ca(2+)-entry) reduced the LPS-induced hypocalcemia. These results suggest that in mice: (i) IL-1 and TNF-α may contribute little to physiological bone-formation, and (ii) a time-lag between IL-1- and TNF-α-stimulated Ca(2+)-entry into cells throughout the body from the circulation and IL-1-stimulated Ca(2+)-release from the bone may cause the observed transient LPS-induced hypocalcemia. Thus, the prime role of bone IL-1 may reside in the supply of Ca(2+) from the bone to cells throughout the body when the need is urgent.
Department of Molecular Regulation, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Xue
X
Deng
Senri
S
Oguri
Hiromi
H
Funayama
Yuko
Y
Ohtaki
Masafumi
M
Ohsako
Zhiqian
Z
Yu
Shunji
S
Sugawara
Yasuo
Y
Endo
D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D016723:Bone Remodeling / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism*; D002118:Calcium / Q000097:blood / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004002:Clodronic Acid / Q000494:pharmacology; D006996:Hypocalcemia / Q000139:chemically induced / Q000188:drug therapy; D007003:Hypoglycemia / Q000139:chemically induced / Q000188:drug therapy; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009543:Nifedipine / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins; D013977:Tibia / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D050071:Bone Density Conservation Agents; D002121:Calcium Channel Blockers; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D009543:Nifedipine; D002118:Calcium