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

Mählich, Daniela; Glasmacher, Anne; Müller, Ilse; Oppermann, Johannes; Grevenstein, David; Eysel, Peer; Heilig, Juliane; Wirth, Brunhilde; Zaucke, Frank; Niehoff, Anja

doi:10.3390/ijms22063073

Cited by 9 publications

(9 citation statements)

References 64 publications

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“…This is in line with the observed elevated cortical thickness in PLS3 OE mice, which might be due to inhibited osteoclastogenesis [16]. Furthermore, the RANKL-RANK pathway plays a crucial role not only in osteoarthritis in general [159][160][161], but seems to be stressed in osteoarthritis patients showing increased PLS3 levels [157]. Further, differentially upregulated pathways in osteoarthritis patients are related to the actin cytoskeleton, endocytosis, TGF-β, MAPK, TNF-α, WNT and general metabolism processes [157].…”

Section: Osteoarthritissupporting

confidence: 79%

Plastin 3 in health and disease: a matter of balance

Wolff

Strathmann

Müller

et al. 2021

Cell. Mol. Life Sci.

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For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.

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Section: Osteoarthritissupporting

confidence: 79%

Plastin 3 in health and disease: a matter of balance

Wolff

Strathmann

Müller

et al. 2021

Cell. Mol. Life Sci.

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“…44 A recent study reported elevated PLS3 in arthritic cartilage of the medial compartment of varus knees. 28 Our finding of elevated PLS3 levels in synovial fluid of knees with isolated ACL injuries appears contrary to what might be expected because isolated ACL tears are thought to be associated with a lower risk of developing osteoarthritis than ACL tears with concomitant meniscal tears. Interestingly, plectin is another protein with findings contrary to what might be expected.…”

Section: Discussioncontrasting

confidence: 99%

Proteomic Profile Analysis of Synovial Fluid in Patients With Anterior Cruciate Ligament Tears

et al. 2022

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Background: Anterior cruciate ligament (ACL) tears are associated with posttraumatic osteoarthritis, but the early biological changes that initiate joint degeneration after this injury are not well characterized. ACL tears typically result in effusion in the knee, which may provide insight into the initial response of the joint to injuries. Hypothesis: Patient- and injury-specific factors are associated with the proteomics of synovial fluid in knees with ACL tears. Study Design: Descriptive laboratory study. Methods: Synovial fluid was collected from 105 patients (38 male, 67 female) with an acute traumatic ACL tear. Patient- and injury-specific factors such as age, sex, body mass index, time from injury, presence/absence of concomitant meniscal tears, and location of concomitant bone bruises (if present) were recorded. The protein concentration of synovial fluid was measured, followed by benchmarking of samples for multi-affinity high-abundance protein depletion. An isotropically labeled high-resolution nano-liquid chromatography with tandem mass spectrometry–based proteomic approach was used to determine the synovial fluid protein profile. Data were processed, quality controlled, and analyzed computationally for each patient and injury factor. Results: The proteomics of synovial fluid from ACL tears was associated with patient sex, injury pattern, and location of bone bruises but not with patient age, body mass index, or time from injury. Knees with an isolated ACL tear had higher glutathione peroxidase 1 (GPX1) and plastin 3 levels than knees with an ACL tear and meniscal tear. A bone bruise on the lateral femoral condyle was associated with elevated leptin and glucose-6-phosphate dehydrogenase (G6PD) levels. A bone bruise on the lateral tibial plateau was associated with decreased GPX1 levels. Male patients had higher matrix metalloproteinase 9 and lower G6PD levels than female patients. Conclusion: Patient sex, injury pattern, and bone bruise location were important determinants of the proteomic profile of effusion resulting from ACL tears. Clinical Relevance: Longitudinal follow-ups to see if and how proteomic differences relate to clinical outcomes and mechanistic studies to assess the role that specific proteins play in the joint are warranted. Ultimately, these investigations could lead to better approaches to predict clinical outcomes and identify possible interventions to optimize outcomes in these patients.

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“…Aberrantly decreased or increased PLS3 level was reported to be linked with the development and/or severity of cancer, bone disorders and neurodegeneration disorders [ 4 ]. The crucial role of PLS3 in the regulation of bone mineral density has drawn attention of researchers during recent years, since pathogenic mutation or knockout of PLS3 caused early-onset osteoporosis while overexpression of PLS3 triggered osteoarthritis [ 16 , 17 ]. Despite mounting evidence that the deficiency of normal PLS3 in patients with pathogenic mutations leads to early-onset osteoporosis, whether abnormal PLS3 level was associated with osteoporosis in individuals without pathogenic mutations remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel splicing mutation and genotype–phenotype correlations in rare PLS3-related childhood-onset osteoporosis

Feng

Zhu

et al. 2022

Orphanet J Rare Dis

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Background X-linked early-onset osteoporosis, caused by mutations in plastin3 (PLS3), is an extremely rare disease characterized by low bone mineral density (BMD) and recurrent osteoporotic fractures. There is limited information on genetic and phenotypic spectrum, as well as genotype–phenotype correlations of the disease. Moreover, whether decreased PLS3 levels were also involved in osteoporosis among subjects without PLS3 pathogenic mutations remains unknown. Methods Whole-exome sequencing and bidirectional Sanger sequencing were performed for screening and validation of pathogenic mutations. Serum biochemical parameters and clinical information of the subjects were retrospectively collected. ELISA and online datasets were utilized to investigate the association between PLS3 expression and BMD. Results We identified a novel splicing mutation (c.892-2A > G) which led to the skipping of exon 9 in a family with X-linked early-onset osteoporosis. Scoliosis represents a potential new phenotype in the patients harboring PLS3 mutations, which may be corrected by brace treatment. Genotype–phenotype analysis reveals that there was no significant difference in BMD z-scores between different types of reported mutations including this study (p = 0.5). There is a marginally significant negative correlation between age and BMD z-score (p = 0.059, r = − 0.30). The conditions of osteoporosis in all patients were improved after bisphosphonates therapy, with mean BMD z-score increased from − 2.9 to − 0.57 (p < 0.0001). Serum PLS3 levels in adolescents and adults without PLS3 pathogenic mutations but representing osteoporosis were also evaluated, while no association was found between bone mineral density and PLS3 levels (p > 0.05). Conclusions Our findings expanded the mutation and phenotype spectrum of the rare disease and highlights the importance of early diagnosis and early treatment with bisphosphonates. More reports of cases with PLS3 mutation and function studies of the gene are warranted to understand genotype–phenotype correlations.

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

Cited by 9 publications

References 64 publications

Plastin 3 in health and disease: a matter of balance

Plastin 3 in health and disease: a matter of balance

Proteomic Profile Analysis of Synovial Fluid in Patients With Anterior Cruciate Ligament Tears

Identification of a novel splicing mutation and genotype–phenotype correlations in rare PLS3-related childhood-onset osteoporosis

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