Regulation of lysosome biogenesis and functions in osteoclasts

Lacombe, Julie; Karsenty, G.; Ferron, Mathieu

doi:10.4161/cc.25825

Cited by 79 publications

(83 citation statements)

References 99 publications

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“…Indeed, the phenotype of the Ostm1-null gray-lethal gl/gl mouse in osteoclasts, immunodeficiency, neuronal cells, and melanosomes can be elucidated by a defective adaptor function endosome/lysosome dispersion mechanism. Normally, the secretory lysosomes produced in osteoclasts (48)(49)(50) participate in the formation of a specific membrane structure, the ruffled border, and regulate secretion of specific proton pumps and enzymes essential for bone matrix degradation (51,52). In Ostm1-null osteoclasts, the lack of Ostm1 vesicles linked to KIF5B cargos would elucidate the virtual absence of ruffled border, resulting in nonfunctional secretory cells, inefficient bone resorption, and osteopetrosis (9).…”

Section: Discussionmentioning

confidence: 99%

Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

Pandruvada

Beauregard

Benjannet

et al. 2016

Molecular and Cellular Biology

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In humans and in mice, mutations in the Ostm1 gene cause the most severe form of osteopetrosis, a major bone disease, and neuronal degeneration, both of which are associated with early death. To gain insight into Ostm1 function, we first investigated by sequence and biochemical analysis an immature 34-kDa type I transmembrane Ostm1 protein with a unique cytosolic tail. Mature Ostm1 is posttranslationally processed and highly N-glycosylated and has an apparent mass of ϳ60 kDa. Analysis the subcellular localization of Ostm1 showed that it is within the endoplasmic reticulum, trans-Golgi network, and endosomes/lysosomes. By a wide protein screen under physiologic conditions, several novel cytosolic Ostm1 partners were identified and validated, for which a direct interaction with the kinesin 5B heavy chains was demonstrated. These results determined that Ostm1 is part of a cytosolic scaffolding multiprotein complex, imparting an adaptor function to Ostm1. Moreover, we uncovered a role for the Ostm1/KIF5B complex in intracellular trafficking and dispersion of cargos from the endoplasmic reticulum to late endosomal/lysosomal subcellular compartments. These Ostm1 molecular and cellular functions could elucidate all of the pathophysiologic mechanisms underlying the wide phenotypic spectrum of Ostm1-deficient mice.

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Section: Discussionmentioning

confidence: 99%

Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

Pandruvada

Beauregard

Benjannet

et al. 2016

Molecular and Cellular Biology

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“…Osteoclast bone resorption unbalanced by bone formation leads to osteoporosis, the most widespread skeletal disorder. Interestingly, studies of osteopetrosis, a class of genetic bone diseases in which osteoclast function or differentiation are compromised, have led to key insights into bone metabolism and have resulted in novel and effective therapeutics to prevent bone loss in osteoporosis and other bone diseases …”

Section: Introductionmentioning

confidence: 99%

Snx10 and PIKfyve are required for lysosome formation in osteoclasts

Sultana

Morse

Picotto

et al. 2019

J of Cellular Biochemistry

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Bone resorption and organelle homeostasis in osteoclasts require specialized intracellular trafficking. Sorting nexin 10 (Snx10) is a member of the sorting nexin family of proteins that plays crucial roles in cargo sorting in the endosomal pathway by its binding to phosphoinositide(3)phosphate (PI3P) localized in early endosomes. We and others have shown previously that the gene encoding sorting Snx10 is required for osteoclast morphogenesis and function, as osteoclasts from humans and mice lacking functional Snx10 are dysfunctional. To better understand the role and mechanisms by which Snx10 regulates vesicular transport, the aim of the present work was to study PIKfyve, another PI3P‐binding protein, which phosphorylates PI3P to PI(3,5)P2. PI(3,5)P2 is known to be required for endosome/lysosome maturation, and the inhibition of PIKfyve causes endosome enlargement. Overexpression of Snx10 also induces accumulation of early endosomes suggesting that both Snx10 and PIKfyve are required for normal endosome/lysosome transition. Apilimod is a small molecule with specific, nanomolar inhibitory activity on PIKfyve but only in the presence of key osteoclast factors CLCN7, OSTM1, and Snx10. This observation suggests that apilimod's inhibitory effects are mediated by endosome/lysosome disruption. Here we show that both Snx10 and PIKfyve colocalize to early endosomes in osteoclasts and coimmunoprecipitate in vesicle fractions. Treatment with 10 nM apilimod or genetic deletion of PIKfyve in cells resulted in the accumulation of early endosomes, and in the inhibition of osteoclast differentiation, lysosome formation, and secretion of TRAP from differentiated osteoclasts. Snx10 and PIKfyve also colocalized in gastric zymogenic cells, another cell type impacted by Snx10 mutations. Apilimod‐specific inhibition of PIKfyve required Snx10 expression, as it did not inhibit lysosome biogenesis in Snx10‐deficient osteoclasts. These findings suggest that Snx10 and PIKfyve are involved in the regulation of endosome/lysosome homeostasis via the synthesis of PI(3,5)P2 and may point to a new strategy to prevent bone loss.

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“…The ruffled border generates an acidic extracellular microenvironment called as resorption lacuna, which is surrounded by an actin ring18. Several acid hydrolases are secreted in the resorption lacuna, which is formed on the bone surface19. Among these acid hydrolases, cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP, also known as ACP5) are highly expressed and secreted by differentiated OCLs.…”

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confidence: 99%

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

Shimada-Sugawara

Sakai

Okamoto

et al. 2015

Sci Rep

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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.

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Regulation of lysosome biogenesis and functions in osteoclasts

Cited by 79 publications

References 99 publications

Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

Snx10 and PIKfyve are required for lysosome formation in osteoclasts

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

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