Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis

Abstract

Bone homeostasis is a complex, multi-step process, which is based primarily on a tightly orchestrated interplay between bone formation and bone resorption that is executed by osteoblasts and osteoclasts (OCLs), respectively. The essential physiological balance between these cells is maintained and controlled at multiple levels, ranging from regulated gene expression to endocrine signals, yet the underlying cellular and molecular mechanisms are still poorly understood. One approach for deciphering the mechanisms that regulate bone homeostasis is the characterization of relevant pathological states in which this balance is disturbed. In this article we describe one such “error of nature,” namely the development of acute recessive osteopetrosis (ARO) in humans that is caused by mutations in sorting nexin 10 (SNX10) that affect OCL functioning. We hypothesize here that, by virtue of its specific roles in vesicular trafficking, SNX10 serves as a key selective regulator of the composition of diverse membrane compartments in OCLs, thereby affecting critical processes in the sequence of events that link the plasma membrane with formation of the ruffled border and with extracellular acidification. As a result, SNX10 determines multiple features of these cells either directly or, as in regulation of cell-cell fusion, indirectly. This hypothesis is further supported by the similarities between the cellular defects observed in OCLs form various models of ARO, induced by mutations in SNX10 and in other genes, which suggest that mutations in the known ARO-associated genes act by disrupting the same plasma membrane-to-ruffled border axis, albeit to different degrees. In this article, we describe the population genetics and spread of the original arginine-to-glutamine mutation at position 51 (R51Q) in SNX10 in the Palestinian community. We further review recent studies, conducted in animal and cellular model systems, that highlight the essential roles of SNX10 in critical membrane functions in OCLs, and discuss possible future research directions that are needed for challenging or substantiating our hypothesis.

Using multi-scale genomics to associate poorly annotated genes with rare diseases

“…Each participant presented with a distinct clinical anomaly and was referred to Istishari Hospital by their respective physicians from various Palestinian regions to undergo exome sequencing for the identification of genetic causes. We established a database of 109 patient exomes who had received a known molecular diagnosis, some of which have been published [ 35 – 37 ]. All of the variants identified to be disease-causing in those patients had been reported as pathogenic/likely pathogenic in the ClinVar database [ 38 ].…”

SNX10 regulates the clearance of mitochondrial proteins and mitochondrial bioenergetics

“…To characterize the mechanisms underlying the normal function of SNX10 and its role in disease development, we generated U2OS cell lines with stable inducible expression of EGFP-tagged wild type (WT) SNX10 or SNX10 having mutations corresponding to ARO-linked SNPs (Y32S, R51P or R51Q), all located in the PX domain 29 of the canonical SNX10 isoform (which contains a full length PX domain unlike the shorter isoform which lacks the first 84 amino acids) (Fig. 1A and Supplementary Fig.…”

Osteopetrosis associated with PLEKHM1 and SNX10 genes, both involved in osteoclast vesicular trafficking

“…Among these variants is a frameshift variant (c.212+1G>T) that was identified in patients suffering from Västerbottenian osteopetrosis, which refers to a cluster of cases in Västerbotten County (Sweden) with an increased disease incidence due to a founder effect [21,24]. Current data show that ARO caused by SNX10 variants is phenotypically heterogeneous [30,31]. This may be due to incomplete penetrance or variable genetic expression, as no genotype/phenotype correlations could be established [21,32].…”

“…However, there is emerging evidence that SNX10 plays a role outside the skeletal system, i.e. in cancer, metabolic diseases and chaperone-mediated autophagy [30,[38][39][40].…”