👤 Minju Gal

Fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis of arthritis. However, the impact of small extracellular vesicles (sEVs) secreted by FLSs on osteoclastogenesis remains incompletely understood. In this study, we aimed to investigate the role of tumor necrosis factor (TNF)- and lysophosphatidic acid (LPA)-activated FLSs in sEV-mediated release of osteoclastogenic miRNAs and elucidate their functional contribution to osteoclastogenesis. Stimulation of SW982 cells with LPA or TNF significantly increased sEV secretion. TNF upregulated autotaxin expression and promoted sEV release; however, small interfering RNA (siRNA)-mediated knockdown (KD) of LPAR1 attenuated the increase in sEV release induced by the TNF-autotaxin-LPA axis. Notably, stimulation with TNF or LPA elevated syntenin-1 expression without altering its mRNA level. Furthermore, KD of the syntenin-1 gene (SDCBP) suppressed the LPA-induced increase in sEV release, indicating that syntenin-1 may mediate sEV secretion induced by the TNF-autotaxin-LPA-LPAR1 axis. sEVs derived from TNF- or LPA-treated SW982 cells stimulated osteoclastogenesis. We identified miR-31-5p as an osteoclastogenic miRNA enriched in sEVs. Expression levels of miR-31-5p in sEVs from TNF- and LPA-stimulated rheumatoid arthritis (RA) FLSs were significantly higher than in those from unstimulated RA FLSs. Treatment with a miR-31-5p mimic enhanced osteoclastogenesis by targeting large tumor suppressor kinase 2 (LATS2), whereas treatment with its inhibitor suppressed the sEV-mediated promotion of osteoclastogenesis. These findings reveal a mechanism by which TNF- and LPA-activated FLSs may facilitate sEV-mediated delivery of osteoclastogenic miRNAs, such as miR-31-5p, to osteoclast precursors, thereby contributing to osteoclast formation and bone destruction. Show less

Neuronal ceroid lipofuscinoses (NCL) are storage diseases leading to severe somatic and mental deterioration with blindness and death. To date, there are no therapeutic options. Juvenile NCL (JNCL), also known as Batten's disease, is one of the most prevalent forms of NCL. A 6-year-old boy with the primary diagnosis of retinitis pigmentosa was examined. The parents reported a rapid deterioration of vision during the past months. In view of this history, additional, non-ophthalmological diagnostic procedures have been performed (peripheral blood smear, molecular genetics). The eye examination showed a considerable reduction of visual acuity, a concentric visual field constriction, an extinguished electroretinogram and a bull's eye maculopathy. The peripheral blood smear revealed vacuolated lymphocytes. Molecular genetic investigation confirmed the diagnosis of juvenile NCL by detecting a homozygous (1-kb deletion of the CLN3-gene). The ophthalmologist plays a key role for an early diagnosis of juvenile NCL. An early diagnosis is important for the affected families because only then they can handle this stroke of fate. Show less

Carbamoyl phosphate synthetase I (CPS1) deficiency is an autosomal recessive metabolic disorder affecting the first enzymatic step of urea cycle. We report a consanguineous family in which the index patient died at 11 days of age from a severe form of CPS1 deficiency. Initial diagnosis was based on clinical histopathological, and enzymatic investigations. Direct sequencing of the complete CPS1 coding region revealed a disease-associated homozygous Thr544Met mutation in CPS1. On the basis of the molecular data, prenatal diagnosis was established for genomic DNA and performed at gestational week 12, after chorionic villus sampling. The fetus was homozygous for the Thr544Met mutation, and termination of pregnancy was elected. Histopathological signs of the hepatocellular metabolic disorder similar to that of the index patient were found in fetal liver thus giving morphological evidence for this hereditary error of urea cycle function as early as gestational week 12. Show less