PLS3 Mutations Cause Severe Age and Sex-Related Spinal Pathology

Abstract

Objective: Mutations in the X-chromosomal PLS3-gene, encoding Plastin 3, lead to severe early-onset osteoporosis, suggesting a major role for PLS3 in bone metabolism. However, the consequences of abnormal PLS3 function in bone and other tissues remain incompletely characterized. This study evaluated spinal consequences of aberrant PLS3 function in patients with PLS3 mutations. Design: A cross-sectional cohort study with spinal magnetic resonance imaging of 15 PLS3 mutation-positive (age range 9-77 years) and 13 mutation-negative (9-70 years) subjects. Images were reviewed for spinal alignment, vertebral heights and morphology, intervertebral disc changes and possible endplate deterioration. Results: Vertebral changes were significantly more prevalent in the mutation-positive subjects compared with the mutation-negative subjects; they were most abundant in upper thoracic spine, and in all age groups and both sexes, although more prominent in males. Difference in anterior vertebral height reduction was most significant in T5 and T6 (p = 0.046 and p = 0.041, respectively). Mid-vertebral height reduction was most significant in T3 and T5 (p = 0.037 and p = 0.005, respectively), and, for male mutation-positive subjects only, in T4 and T6-10 (p = 0.005-0.030 for each vertebra). Most of the abnormal vertebrae were biconcave in shape but thoracic kyphosis or lumbar lordosis were unchanged. Vertebral endplates were well-preserved in the mutation-positive subjects with even fewer Schmorl nodes than the mutation-negative subjects (10 vs. 16). Conclusions: Compromised PLS3 function introduces severe and progressive changes to spinal structures that are present already in childhood, in both sexes and most abundant in upper thoracic spine. Cartilaginous structures are well-preserved.

Expression and Localization of Thrombospondins, Plastin 3, and STIM1 in Different Cartilage Compartments of the Osteoarthritic Varus Knee

“…Pls3 KO mice demonstrated an osteoporotic phenotype, while PLS3 overexpressing mice showed hyperostosis [ 26 ]. PLS3 was detected in the dendrites of osteocytes [ 59 ], and it has been suggested that PLS3 might be involved in the mechanotransduction [ 18 , 27 , 28 , 60 ] and seems also to be involved in osteoclastogenesis [ 26 ]. Interestingly, we found that PLS3 was mainly located at the upper zone of the OA cartilage.…”

“…There are only very few studies analyzing the role of PLS3 in cartilage. Mäkitie et al [ 28 ] investigated spinal changes in patients with PLS3 mutations. Although the spinal structures demonstrated severe and progressive alterations in, e.g., vertebra height and shape, pathologies at the intervertebral discs were not present.…”

Plastin 3 in health and disease: a matter of balance

“…To analyze the proposed functions of PLS3 regarding mechanotransduction [5,15,108,120,143,144,148], Ca 2+ regulation [23,33,149], osteoblastic bone mineralization [15,120,126,131,134,143,144,150], osteoclastogenesis [16] and vesicular trafficking [15,16,61,151], various PLS3 mutations have been investigated and mouse model studies established to specifically investigate the effect of PLS3 loss or overexpression [16].…”

“…So far, less is known about the effect of PLS3 deletions on cartilage. Another study has shown no effect on the intervertebral disc of osteoporosis patients linked to loss of function and PLS3 deletions [148]. The influence of PLS3 overexpression, PLS3 loss, and PLS3 mutations on articular cartilage itself remains elusive and the underlying mechanism affecting cartilage health still needs to be explored.…”

Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020

“…Furthermore, it is difficult to “quality control” the data that is interrogated. For example, there are several papers that assign different activities to PLS3 but no clear function for the protein has yet emerged and it is still unclear whether its major role is in osteoblasts or osteoclasts or both ( 85 ).…”