Brain-type creatine kinase has a crucial role in osteoclast-mediated bone resorption

Abstract

Osteoclasts differentiate from precursor cells of the monocyte-macrophage lineage and subsequently become activated to be competent for bone resorption through programs primarily governed by receptor activator of nuclear factor-kappaB ligand in cooperation with macrophage colony-stimulating factor. Proteins prominently expressed at late phases of osteoclastogenesis and with a supportive role in osteoclast function are potential therapeutic targets for bone-remodeling disorders. In this study, we used a proteomics approach to show that abundance of the brain-type cytoplasmic creatine kinase (Ckb) is greatly increased during osteoclastogenesis. Decreasing Ckb abundance by RNA interference or blocking its enzymatic activity with a pharmacological inhibitor, cyclocreatine, suppressed the bone-resorbing activity of osteoclasts grown in vitro via combined effects on actin ring formation, RhoA GTPase activity and vacuolar ATPase function. Activities of osteoclasts derived from Ckb-/- mice were similarly affected. In vivo studies showed that Ckb-/- mice were better protected against bone loss induced by ovariectomy, lipopolysaccharide challenge or interleukin-1 treatment than wild-type controls. Furthermore, administration of cyclocreatine or adenoviruses harboring Ckb small hairpin RNA attenuated bone loss in rat and mouse models. Our findings establish an important role for Ckb in the bone-resorbing function of osteoclasts and underscore its potential as a new molecular target for antiresorptive drug development.

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

“…In retina photoreceptor cells, BCK may play an equally important role, but rather in synaptic transmission at the synaptic terminal (Linton et al 2010) or for cGMP resynthesis in the rod outer segments (Hemmer et al 1993). Some studies have evidenced a role of BCK in cartilage and bone formation, as well as bone resorption (Funanage et al 1992;Chang et al 2008). In this context, BCK was also found in extracellular matrix vesicles that initiate mineralization for bone formation, and where many plasma membrane associated proteins are preserved (Sekrecka-Belniak et al 2010), although its precise role at that location remains unclear.…”

Adenylate cyclase and calmodulin-dependent kinase have opposite effects on osteoclastogenesis by regulating the PKA-NFATc1 pathway

“…(25,26) Isolated bone marrow cells were cultured in a modified essential medium (a-MEM) containing 10% fetal bovine serum (FBS) overnight on culture dishes. Nonadherent cells were further cultured for 3 days in the presence of 5 ng/mL of M-CSF.…”

Creatine kinase B is necessary to limit myoblast fusion during myogenesis

“…In addition, cell migration, a process dependent on actin remodeling, was not altered in CKB siRNA-treated muscle cells, further suggesting that actin polymerization is not disrupted at this stage of myogenesis. In contrast, genetic or pharmacological inhibition of CKB results in changes of the actin cytoskeleton in macrophages, osteoclasts, and cardiomyocytes (12,15,35). Several factors could account for this difference between skeletal muscle cells and other cell types.…”