Prime role of bone IL-1 in mice may lie in emergency Ca2Â +-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 Ca2 +-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 Ca2 +-entry into cells throughout the body from the circulation and IL-1-stimulated Ca2 +-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 Ca2 + from the bone to cells throughout the body when the need is urgent.

► IL-1 and TNF-α are thought to be important regulators of bone-remodeling. ► Here, we detected no growth or tibial defects in most mice lacking IL-1 and/or TNF-α. ► Sub-lethal LPS induced transient hypocalcemia mediated by both IL-1 and TNF-α. ► This occurred via Ca2 +-entry into cells preceding IL-1-induced Ca2 +-release from bone. ► The prime role of IL-1 in bone may be to shift Ca2 + from bone into the body's cells.