Skeletal pathologies caused by PLS3 inactivation are predominantly associated with impaired cortical bone integrity.

The identification of pathogenic PLS3 variants in individuals with X-linked osteoporosis (XLO) has demonstrated the importance of the actin-bundling protein plastin-3 for skeletal integrity. We and others have previously reported that Pls3-deficient mice display a skeletal phenotype that unexpectedly affects only the cortical bone compartment. To better characterize the impact of PLS3 inactivation on bone (micro-)architectural parameters in humans, we retrospectively analyzed skeletal parameters obtained from male XLO patients and compared them to corresponding data from male individuals with genetically diagnosed osteogenesis imperfecta type I (OI-I). We observed no major differences between XLO and OI-I patients in baseline characteristics, laboratory parameters, or bone mineral density measurements by dual-energy X-ray absorptiometry (DXA). However, there was a significant difference between the two groups observed by high resolution peripheral quantitative computed tomography (HRpQCT). More specifically, XLO patients displayed significantly reduced cortical bone parameters, compared to both normal reference ranges and OI-I, especially at the distal radius. We also analyzed female heterozygous carriers of (likely) pathogenic PLS3 alleles, who were less affected compared to male XLO patients. However, two of them displayed osteoporotic fractures at a postmenopausal age, thus treatment with romosozumab, a monoclonal antibody targeting sclerostin, was initiated and appeared to be effective. Since another sclerostin-neutralizing antibody is currently studied for the treatment of OI patients, we crossed Pls3-deficient mice with mice carrying a high bone mass allele of Lrp5 (Lrp5A213V), which serves as a molecular mimic of anti-sclerostin therapy. We found that the presence of the Lrp5A213V allele led to significantly increased cortical and trabecular bone mass not only in wildtype but also in Pls3-deficient mice. Taken together, our data raise the hypothesis that PLS3 inactivation predominantly affects cortical bone parameters in mice and humans and that anti-sclerostin therapy could be effective for the treatment of XLO.