Histone Acetylation Influences the Activity of Sox9-related Transcriptional Complex

Chondrocyte differentiation is the fundamental process in skeletal development. From the mesenchymal condensation of chondroprogenitors to the hypertrophic maturation of chondrocytes, chondrogenesis is sequentially regulated by cross-talk among transcription factors, growth factors, and chromatin structure. The master transcription factor Sry-type HMG box (Sox) 9 has an essential role in the expression of chondrogenic genes through the association with Sox9-binding sites on its target genes. Several transcription factors and coactivators, such as Scleraxis/E47 and p300, cooperatively modulate the Sox9-dependent transcription by interacting with Sox9. The Sox9-related transcriptional apparatus activates its target gene expression through p300-mediated histone acetylation on chromatin. The transforming growth factor (TGF)-β superfamily also plays a key role in chondrocyte differentiation. The TGF-β-regulated Smad3/4 complex activates Sox9-dependent transcription on chromatin by associating with Sox9 itself, and by recruiting p300 onto Sox9. These findings suggest that the epigenetic status including histone modification and chromatin structure, directly influences Sox9-regulated chondrocyte differentiation. In this article, we review the regulators of Sox9 expression itself, modulators of posttranslational Sox9 function, and Sox9-associating factors in the Sox9-dependent epigenetic regulation during chondrogenesis

Stress responsive miR-23a attenuates skeletal muscle atrophy by targeting MAFbx /atrogin-1

Muscle atrophy occurs in many pathological states and results primarily from accelerated protein degradation by the ubiquitin-proteasome pathway. We used dexamethasone to induce muscle wasting and investigated the role of a microRNA (miRNA) in the control of muscle-specific E3 ubiquitin ligase MAFbx/atrogin-1. Here we show that miR-23a suppresses MAFbx/atrogin-1 translation by binding to 3'UTR of the mRNA. Furthermore, ectopic expression of miR-23a is sufficient to protect myocytes from atrophy in vitro and in vivo in response to dexamethasone treatment, and heat stress-induced miR-23a protects muscle from dexamethasone-induced muscle atrophy. Our surprising discovery of the physiological role of miR-23a in preventing the atrophy program should lay the basis not only for further understanding of the mechanisms of muscle wasting in diverse diseases, but also for developing novel therapies for these debilitating conditions

CD34 positive cells as endothelial progenitor cells in biology and medicine

CD34 is a cell surface antigen expressed in numerous stem/progenitor cells including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which are known to be rich sources of EPCs. Therefore, regenerative therapy using CD34+ cells has attracted interest for application in patients with various vascular, ischemic, and inflammatory diseases. CD34+ cells have recently been reported to improve therapeutic angiogenesis in a variety of diseases. Mechanistically, CD34+ cells are involved in both direct incorporation into the expanding vasculature and paracrine activity through angiogenesis, anti-inflammatory, immunomodulatory, and anti-apoptosis/fibrosis roles, which support the developing microvasculature. Preclinical, pilot, and clinical trials have well documented a track record of safety, practicality, and validity of CD34+ cell therapy in various diseases. However, the clinical application of CD34+ cell therapy has triggered scientific debates and controversies in last decade. This review covers all preexisting scientific literature and prepares an overview of the comprehensive biology of CD34+ cells as well as the preclinical/clinical details of CD34+ cell therapy for regenerative medicine

Visceral-to-subcutaneous fat ratio is a possible prognostic factor for type 1 endometrial cancer

[Background] Associations have been observed between obesity defined by the body mass index (BMI) and the incidence of endometrial cancer. However, the impact of obesity on the prognosis of endometrial cancer is not yet clear. Recently, visceral fat has been considered to have a greater impact on malignant disease in obese patients than subcutaneous fat. In this study, we investigated the association between prognostic factors of type 1 and type 2 endometrial cancer and obesity parameters. [Methods] The impacts of clinical factors on the progression-free survival (PFS) and overall survival (OS) were analyzed retrospectively in 145 primary endometrial cancer patients. The factors included age, BMI, pathological findings, Federation of Gynecology and Obstetrics (FIGO) stage, status of lymph node metastasis, and the amounts of visceral and subcutaneous fat obtained from computed tomography (CT) data. [Results] Only the visceral-to-subcutaneous fat ratio (V/S ratio) (cutoff value 0.5) corresponded to a significant difference in OS and PFS in type 1 endometrial cancer (p = 0.0080, p = 0.0053) according to the results of log-rank tests of Kaplan–Meier curves. The COX regression univariate analysis revealed that only the V/S ratio was a significant prognostic factor for PFS, but not OS (p = 0.033 and p = 0.270, respectively). [Conclusion] A V/S ratio > 0.5 is a possible factor for poor prognosis in type 1 endometrial cancer. Further research is needed to investigate the preventive and therapeutic effects of reducing visceral fat on the prognosis of this type of cancer

Smad3 activates the Sox9-dependent transcription on chromatin

Transforming growth factor (TGF)-β has an essential role for the Sry-type high-mobility-group box (Sox)-regulated chondrogenesis. Chondrogenic differentiation is also controlled by chromatin-mediated transcription. We have previously reported that TGF-β-regulated Smad3 induces chondrogenesis through the activation of Sox9-dependent transcription. However, the cross-talk between TGF-β signal and Sox9 on chromatin-mediated transcription has not been elucidated. In the present study, we investigated the activity of Smad3, Sox9, and coactivator p300 using an in vitro chromatin assembly model. Luciferase reporter assays revealed that Smad3 stimulated the Sox9-mediated transcription in a TGF-β-dependent manner. Recombinant Sox9 associated with phosphorylated Smad3/4 and recognized the enhancer region of type II collagen gene. In vitro transcription and S1 nuclease assays showed that Smad3 and p300 cooperatively activated the Sox9-dependent transcription on chromatin template. The combination treatment of phosphorylated Smad3, Sox9, and p300 were necessary for the activation of chromatin-mediated transcription. These findings suggest that TGF-β signal Smad3 plays a key role for chromatin remodeling to induce chondrogenesis via its association with Sox9

Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification

<p>Abstract</p> <p>Background</p> <p>Chondrogenesis and subsequent endochondral ossification are processes tightly regulated by the transcription factor Sox9 (SRY-related high mobility group-Box gene 9), but molecular mechanisms underlying this activity remain unclear. Here we report that coactivator-associated arginine methyltransferase 1 (CARM1) regulates chondrocyte proliferation via arginine methylation of Sox9.</p> <p>Results</p> <p>CARM1-null mice display delayed endochondral ossification and decreased chondrocyte proliferation. Conversely, cartilage development of CARM1 transgenic mice was accelerated. CARM1 specifically methylates Sox9 at its HMG domain <it>in vivo </it>and <it>in vitro</it>. Arg-methylation of Sox9 by CARM1 disrupts interaction of Sox9 with beta-catenin, regulating <it>Cyclin D1 </it>expression and cell cycle progression of chondrocytes.</p> <p>Conclusion</p> <p>These results establish a role for CARM1 as an important regulator of chondrocyte proliferation during embryogenesis.</p