Rab27A Regulates Transport of Cell Surface Receptors Modulating Multinucleation and Lysosome-Related Organelles in Osteoclasts

Abstract

Rab27A regulates transport of lysosome-related organelles (LROs) and release of secretory granules in various types of cells. Here, we identified up-regulation of Rab27A during differentiation of osteoclasts (OCLs) from bone-marrow macrophages (BMMs), by DNA microarray analysis. Rab27A deficiency in OCLs, using small interfering RNA (siRNA) knockdown in RAW-D cell line or BMMs derived from ashen mice, which display genetic defects in Rab27A expression, induced multinucleated and giant cells. Upon stimulation with macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL), essential cytokines for OCL differentiation, phosphorylation levels of extracellular signal-regulated kinase (Erk), proto-oncogene tyrosine-protein kinase (Src), and p-38 were slightly enhanced in ashen BMMs than in wild-type BMMs. The cell surface level of c-fms, an M-CSF receptor, was slightly higher in ashen BMMs than in wild-type BMMs, and down-regulation of RANK, a RANKL receptor, was delayed. In addition to receptors, OCLs derived from ashen mice exhibited aberrant actin ring formation, abnormal subcellular localization of lysosome-associated membrane protein (LAMP2) and cathepsin K (CTSK), and marked reduction in resorbing activity. Thus, these findings suggest that Rab27A regulates normal transport of cell surface receptors modulating multinucleation and LROs in OCLs.

PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis

“…However, there is no evidence of defective bone resorption in such humans and mice. Similarly, mutations of RAB27 and its effectors, which control exocytosis of secretory lysosomes in Griscelli's syndrome and respective mouse models, have no effect on osteoclast function (20). In contrast, inhibition of intracellular trafficking of lysosomes and their fusion with the plasma membrane in osteoclasts attenuate the ruffled border formation and bone resorption ( Figures 4 and 5 and previous reports, refs .…”

“…Ashen mice demonstrates that RAB27A does not directly regulate lysosome secretion during bone resorption (20). Moreover, Chocolate mice harboring a spontaneous mutation in RAB38, which is essential for the biogenesis of lysosome-related organelles, have normal osteoclast differentiation and function (21).…”

Actin-binding protein coronin 1A controls osteoclastic bone resorption by regulating lysosomal secretion of cathepsin K

“…As previously reported, small guanosin-5′-triphosphatase (GTPases) Rab7 and Rab27a are necessary for ruffled border formation and/or lysosomal secretion in osteoclasts1213. Furthermore, the localization of Rab7 and LC3 are abnormal, and cathepsin K secretion is significantly decreased in Atg5-deficient osteoclasts21.…”

MiR-124 Attenuates Osteoclastogenic Differentiation of Bone Marrow Monocytes Via Targeting Rab27a

“…In a previous report, the researchers found that Rab27a-deficient osteoclasts showed a markedly impaired bone resorption activity, indicating the important role of Rab27a in maintaining the normal functions of osteoclasts [35,36]. They also showed that depletion of Rab27a results in abnormal phenotypes in osteoclasts.…”