Plakophilin-3 Is Required for Late Embryonic Amphibian Development, Exhibiting Roles in Ectodermal and Neural Tissues

The p120-catenin family has undergone a significant expansion during the evolution of vertebrates, resulting in varied functions that have yet to be discerned or fully characterized. Likewise, members of the plakophilins, a related catenin subfamily, are found throughout the cell with little known about their functions outside the desmosomal plaque. While the plakophilin-3 (Pkp3) knockout mouse resulted in skin defects, we find larger, including lethal effects following its depletion in Xenopus. Pkp3, unlike some other characterized catenins in amphibians, does not have significant maternal deposits of mRNA. However, during embryogenesis, two Pkp3 protein products whose temporal expression is partially complimentary become expressed. Only the smaller of these products is found in adult Xenopus tissues, with an expression pattern exhibiting distinctions as well as overlaps with those observed in mammalian studies. We determined that Xenopus Pkp3 depletion causes a skin fragility phenotype in keeping with the mouse knockout, but more novel, Xenopus tailbud embryos are hyposensitive to touch even in embryos lacking outward discernable phenotypes, and we additionally resolved disruptions in certain peripheral neural structures, altered establishment and migration of neural crest, and defects in ectodermal multiciliated cells. The use of two distinct morpholinos, as well as rescue approaches, indicated the specificity of these effects. Our results point to the requirement of Pkp3 in amphibian embryogenesis, with functional roles in a number of tissue types

Metalloproteinases and their inhibitors—diagnostic and therapeutic opportunities in orthopedics

Matrix metalloproteinases (MMPs) and related enzymes (ADAMs, ADAMTS) and their inhibitors control matrix turnover and function. Recent advances in our understanding of musculoskeletal conditions such as tendinopathy, arthritis, Dupuytren's disease, degenerative disc disease, and bone and soft tissue healing suggest that MMPs have prominant roles. Importantly, MMPs are amenable to inhibition by cheap, safe, and widely available drugs such as the tetracycline antibiotics and the bisphosphonates. This indicates that these MMP inhibitors, if proven effective for any novel indication, may be quickly brought into clinical practice

Plakophilin 1-deficient cells upregulate SPOCK1: implications for prostate cancer progression

Plakophilin (PKP) 1 is frequently downregulated in prostate cancer and therefore may play a tumor-suppressive role. In the present study, we stably knocked down PKP1 in the non-neoplastic, prostatic BPH-1 cell line. In the PKP1-deficient cells, the expression of keratin 14 was lost, and the apoptosis rate was significantly reduced indicating that the cells acquired new biological capabilities. Moreover, we analyzed the gene expression profile of the PKP1-deficient BPH-1 cells. Among the genes that were significantly altered upon PKP1 knockdown, we noticed several extracellular matrix (ECM)-related genes and identified sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1/testican-1) as a gene of interest. SPOCK1 is a component of the ECM and belongs to a matricellular protein family named secreted protein, acidic, cysteine-rich (SPARC). The role of SPOCK1 in prostate cancer has not been clearly elucidated. We analyzed SPOCK1 mRNA expression levels in different cancer databases and characterized its expression in 136 prostatic adenocarcinomas by immunohistochemistry and western blot. SPOCK1 revealed a cytoplasmic localization in the glandular epithelium of the prostate and showed a significant upregulation of mRNA and protein in prostate tumor samples. Our findings support the hypothesis that PKP1 may have a tumor-suppressive function and suggest an important role of SPOCK1 in prostate tumor progression. Collectively, altered expression of PKP1 and SPOCK1 appears to be a frequent and critical event in prostate cancer

Plakophilin-associated RNA-binding proteins in prostate cancer and their implications in tumor progression and metastasis

<p>Both plakophilins (PKP) 1 and 3 play a role in the progression of prostate cancer. The RNA-binding proteins (RBPs) GAP-SH3-binding protein (G3BP), fragile-X-related protein 1 (FXR1), poly(A)-binding protein, cytoplasmic 1 (PABPC1), and up-frameshift factor 1 (UPF1) are associated with PKP3. All these RBPs have an impact on RNA metabolism. Until recently, the PKP-associated RBPs have not been analyzed in prostate cancer. In the current study, we showed by affinity purification that the PKP3-associated RBPs were also binding partners of PKP1. We examined the expression of PKP1/3-associated RBPs and PKP1/3 in prostate cell lines, tumor-free prostate, and 136 prostatic adenocarcinomas by immunofluorescence and immunoblot. All four RBPs G3BP, FXR1, UPF1, and PABPC1 were expressed in the glandular epithelium of the normal prostate. PKP1 and FXR1 were strongly reduced in tumor tissues with Gleason score >7 and diminished expression of PKP1 and FXR1 also appeared to be associated with a metastatic phenotype. Additionally, the predominant nuclear localization of UPF1 in normal glandular cells and low grade tumors was switched to a more cytoplasmic pattern in carcinomas with Gleason score >7. Our findings suggest that PKP1 and FXR1 may have a tumor-suppressive function and are downregulated in more aggressive tumors. Collectively, PKP1/3-associated RBPs FXR1 and UPF1 may have a functional role in prostate cancer progression and metastasis and highlight the potential importance of posttranscriptional regulation of gene expression and nonsense-mediated decay in cancer.</p>

Bone-tendon and bone-ligament interface

Reconstruction or repair of ligaments and tendons to bone, following injury, to improve joint function is a very common surgical procedure in orthopedics. The most common surgical ligament reconstruction in humans is anterior cruciate ligament (ACL) reconstruction. Because ACL is not amenable to repair after tear, replacement of the ligament using autograft or allograft tissue is currently the treatment of choice for young and active patients. On the other hand, surgical reattachment to bone is the most reliable treatment in case of rotator cuff tendon tears. Tendon grafting or repair to bone is performed during hand, foot, and ankle surgery. Nowadays, ACL reconstruction and repair of rotator cuff tendon tears are the most commonly performed surgical procedures for soft tissue injuries in orthopedics. © 2014 Springer-Verlag London. All rights are reserved