Dynein Light Chain LC8 Inhibits Osteoclast Differentiation and Prevents Bone Loss in Mice

Abstract

NF-κB is one of the key transcription factors activated by receptor activator of NF-κB ligand (RANKL) during osteoclast differentiation. The 8-kDa dynein L chain (LC8) was previously identified as a novel NF-κB regulator. However, its physiological role as an NF-κB inhibitor remains elusive. In this study, we showed the inhibitory role of LC8 in RANKL-induced osteoclastogenesis and signaling pathways and its protective role in osteolytic animal models. LC8 suppressed RANKL-induced osteoclast differentiation, actin ring formation, and osteoclastic bone resorption. LC8 inhibited RANKL-induced phosphorylation and subsequent degradation of IκBα, the expression of c-Fos, and the consequent activation of NFATc1, which is a pivotal determinant of osteoclastogenesis. LC8 also inhibited RANKL-induced activation of JNK and ERK. LC8-transgenic mice exhibited a mild osteopetrotic phenotype. Moreover, LC8 inhibited inflammation-induced bone erosion and protected against ovariectomy-induced bone loss in mice. Thus, our results suggest that LC8 inhibits osteoclast differentiation by regulating NF-κB and MAPK pathways and provide the molecular basis of a new strategy for treating osteoporosis and other bone diseases.

Dehydrocostus lactone suppresses osteoclast differentiation by regulating NFATc1 and inhibits osteoclast activation through modulating migration and lysosome function

“…Ovariectomy (OVX) and microcomputed tomography were carried out as previously described in Kim et al (35). Eight-week-old C57BL/6 female mice were randomly divided into the following groups (n = 5 in each group): sham-treatment, OVX, and OVX followed by DL treatment.…”

Multivalent IDP assemblies: Unique properties of LC8‐associated, IDP duplex scaffolds

“…Additionally, in vivo studies of LC8-IDP duplexes are complicated by the ubiquitous nature of LC8 and the presence of multiple LC8 binding sites. Mice deficient in LC8 exhibit developmental defects [58, 92] and Drosophila with reduced LC8 levels die in early embryonic stages of development [93, 94]. Many LC8 binding partners contain multiple binding sites that must be fully removed in order to study the functional impact of LC8 binding in vivo , which becomes challenging when there is ambiguity in identifying all binding motifs.…”

TRP14 Inhibits Osteoclast Differentiation via Its Catalytic Activity

“…We previously unraveled the mechanism underlying the redox-dependent regulation of TNF-␣-induced NF-B activation, in which ROS oxidize LC8 to a homodimer linked by a reversible intermolecular disulfide bond, which promotes its dissociation from IB␣, allowing IB␣ to be phosphorylated and degraded and resulting in NF-B activation (20,21). Recently, we also showed that LC8 inhibits RANKL-induced osteoclastogenesis by regulating NF-B and protects against inflammation-induced or ovariectomy-induced bone loss in mice (31). Thus, it is likely that TRP14 attenuates OC differentiation by inhibiting NF-B through controlling the redox status of LC8.…”

“…Growing evidence suggests that RANKL induces transient production of reactive oxygen species (ROS) that mediate OC differentiation, and activation of NF-B and MAPKs is regulated by cellular redox change (26)(27)(28)(29)(30). We recently showed that LC8 inhibits RANKLinduced OC differentiation by suppressing NF-B and prevents inflammation-induced bone erosion (31). Thus, we sought to evaluate whether a novel cellular redox regulator, TRP14, regulates RANKL-induced activation of NF-B and MAPKs and subsequent osteoclast differentiation by using RAW 264.7 macrophage cells with ectopic expression of wild-type TRP14 and a catalytically inactive mutant, as well as its small interfering RNA.…”