BoneKEy Reports | BoneKEy Watch

Uncovering the molecular and genetic basis of osteopetrosis

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DOI:10.1038/bonekey.2012.131

The life-threatening failure of osteoclast function and differentiation in osteopetrosis is, in 70% of cases, due to defects in the genes involved in maintaining an acidic pH at the ruffled border – the interface between bone and osteoclasts. An acidic environment is crucial to bone resorption, and failure to keep the pH low leads to widespread defects, including blindness and deafness and, ultimately, bone marrow failure. Aker et al. investigated eight infants with osteopetrosis, revealing that they had a missense mutation in their SNX10 gene, which led to overexpression of the SNX10 protein and an altered intracellular distribution.

Specifically, the endosomal/lysosomal pathway was disrupted, causing the formation of large intracellular vacuoles in osteoclasts, which were found to contain large amounts of fluorescent dextran. This resulted in small osteoclasts that had a much reduced capacity for bone resorption. Normally the SNX10 protein appears to help process the V-ATPase complex from the Golgi to the ruffled border; mutations in SNX10 result in a failure to acidify resorption lacuna.

Editor's comment: This study identifies SNX10 mutations as an additional cause of osteopetrosis. Because the impact of these mutations can be completely reversed by bone marrow transplantation, screening for an SNX10 mutation is warranted in any molecularly undefined infants who show acidification failure of osteoclasts.

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