Abstract
An increase of serum creatine kinase (CK) has been observed in clinical studies of nitrogen-containing aminobisphosphonates (N-BPs). Osteoclasts are thought to be the source of the CK, but there is no clear evidence for the hypothesis. In this study, CK release from rabbit osteoclasts induced by N-BPs was examined in an in vitro culture system. Rabbit bone-derived cells were cultured for 3 days on the N-BPs pretreated cortical bone slices. CK activity in the culture medium was measured at 3 days of culture. The CK activity was increased with all N-BPs at concentrations at which showed antiresorptive activity over 60% inhibition of C-terminal cross-linking telopeptide of type I collagen (CTX-1) release. The maximum induction of CK activity was 2.6 times the control level. The lowest N-BP concentration inducing CK release was 3 times lower than that required to decrease the osteoclast number. Bafilomycin A1, an inhibitor of vacuolar H+-ATPase, abrogated all N-BP actions, including CK release. Bone-derived cells except osteoclasts were insensitive to bafilomycin A1, suggesting that osteoclasts were the source of CK. Regarding the time course, CK release occurred after a 1 day lag time and increased steadily until day 3 of culture. These results show that CK release is induced by N-BPs from osteoclasts at concentrations at which N-BPs show antiresorptive activity over 60% inhibition of CTX-1 release in vitro. These findings explain the mechanism of the CK increase induced by clinical use of N-BPs.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-0848-3) contains supplementary material, which is available to authorized users.
Highlights
Creatine kinase (CK) is a dimeric enzyme of about 86 kDa that catalyzes the reaction of creatine and adenosine triphosphate (ATP) to form phosphocreatine and adenosine diphosphate (ADP), a crucial reaction for cellular energy generation and metabolism (Wallimann et al 1992)
Release of bone-bound nitrogen-containing aminobisphosphonates (N-BPs) is promoted by vacuolar H+-ATPase, which is localized along the ruffled borders of osteoclasts and pumps protons out onto the bone surface, and this release can be inhibited by inhibitors of V-ATPase such as bafilomycin A1 (Takami et al 2003)
Significant CK release was occurred all tested N-BPs at concentrations giving over 60% inhibition of CTX-1 level
Summary
Creatine kinase (CK) is a dimeric enzyme of about 86 kDa that catalyzes the reaction of creatine and adenosine triphosphate (ATP) to form phosphocreatine and adenosine diphosphate (ADP), a crucial reaction for cellular energy generation and metabolism (Wallimann et al 1992). Giant cells that resorb bone based on synthesis and secretion of acid and degradative enzymes (Teitelbaum 2007), and maintain a high energy state for active bone resorption (Hazama et al 2009). N-BPs have a nitrogen-containing side chain on the central carbon that determines the inhibitory potency for a target enzyme in the mevalonate pathway, farnesyl pyrophosphate (FPP) synthase. Bone-bound N-BPs are internalized by bone-resorbing osteoclasts and reduce the bone resorption activity or viability of the cells through inhibition of FPP synthase. We hypothesized that CK is released from osteoclasts, but not from other cells present in bone To test this hypothesis, we examined CK release induced by N-BPs from rabbit bone-derived cells in vitro, and we assessed the effect of bafilomycin A1 on CK release to determine the source of CK. We examined the time course of CK release after treatment with N-BPs
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