Bone: Role for PLS3 in X-Linked Osteoporosis Revealed

RESEARCH HIGHLIGHTS Nature Reviews Endocrinology 9, 692 (2013); published online 22 October 2013; doi:10.1038/nrendo.2013.209

BONE Role for PLS3 in X-linked osteoporosis revealed

A new study from a Dutch team has remodelling, and possibly mechanosensing. shown that PLS3, which encodes plastin 3 For example, knockdown of pls3 in (an actin-bundling protein) is involved in zebrafish resulted in malformations X-linked osteoporosis. in the development of the craniofacial The identification of a family with bone structure, body axis and tail. These X-linked inheritance of osteogenesis malformations could be reversed with the imperfecta or osteoporosis with fractures administration of human PLS3 mRNA. prompted the research team to conduct a In addition, an analysis of participants broader study of the genetics underlying from the Rotterdam Study showed that osteoporosis. Linkage analysis was a variant of PLS3 seems to be involved undertaken in two families, and targeted in osteoporosis in elderly women from iStockphoto/Thinkstock next-generation sequencing was carried the general population. The variant The research team are currently out in three affected male patients from was associated with reduced BMD and performing experiments to further explain one of the families to sequence all the increased incidence of fracture. “The the involvement of actin bundling in exons on the X chromosome. relative risk of 1.95 is the highest recorded bone remodelling and disease. The team “Our approach led to the identification so far for osteoporosis,” notes Pals. suggests that mutations in PLS3 lead to of a frameshift mutation in a very unlikely However, the association with fracture decreased mechanosensing of osteocytes, candidate gene, PLS3, that is expressed risk was not fully explained by BMD, and which dysregulates bone modelling or in nearly all tissues and was already was not found in elderly male participants, remodelling, resulting in osteoporosis known to be a protective modifier in which suggests that other factors might be and fractures. They are also studying spinal muscular dystrophy,” explains involved in osteoporosis and fractures in mutations and variants in PLS3 in women corresponding author Gerard Pals (VU this population. with unexplained osteoporosis and/or University Medical Center, Netherlands). These findings suggest that the fractures. “In the future, we aim to develop Further analysis using Sanger sequencing formation of actin bundles in osteocytes, therapies based on our findings,” says Pals. of the PLS3 exons in 95 unrelated affected which requires plastin 3, is an important Claire Greenhill men identified a further four families with and previously unknown factor in bone disruptive mutations in this gene. formation and remodelling. Plastin 3 Analysis of zebrafish and of fibroblasts could therefore be an important diagnostic Original article van Dijk, F. S. et al. PLS3 mutations in X-linked cultured from patients found that plastin 3 tool for young male patients with osteoporosis with fractures. N. Engl. J. Med. doi:10.1056/ NEJMoa1308223 is involved in bone formation and unexplained fractures and osteoporosis.