Recent research has identified that miR-539-3p impedes chondrogenic differentiation, yet its specific role and underlying mechanisms in childhood-onset osteoarthritis (OA) remain unclear. This study found that miR-539-3p levels were considerably lower in cartilage samples derived from childhood-onset OA patients compared to the control group. Enhancing miR-539-3p expression or suppressing RUNX2 expression notably reduced apoptosis, inflammation, and extracellular matrix (ECM) degradation in OA chondrocytes. In contrast, reducing miR-539-3p or increasing RUNX2 had the opposite effects. RUNX2 was confirmed as a direct target of miR-539-3p. Further experiments demonstrated that miR-539-3p targeting RUNX2 effectively lessened apoptosis, inflammation, and ECM degradation in OA chondrocytes, accompanied by changes in key molecular markers like reduced caspase-3 and matrix etallopeptidase 13 (MMP-13) levels, and increased B-cell lymphoma 2 (Bcl-2) and collagen type X alpha 1 chain (COL2A1). This study underscores the pivotal role of miR-539-3p in alleviating inflammation and ECM degradation in childhood-onset OA through targeting RUNX2, offering new insights for potential therapeutic strategies against this disease.

• MeSH
• Apoptosis * MeSH
• Chondrocytes * metabolism   pathology   MeSH
• Child MeSH
• Extracellular Matrix * metabolism   pathology   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• MicroRNAs * metabolism   genetics   MeSH
• Adolescent MeSH
• Osteoarthritis * metabolism   pathology   genetics   MeSH
• Core Binding Factor Alpha 1 Subunit * metabolism   genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

• Keywords
• protokol Toronto-Melbourne, protokol Jeruzalém, protokol Belfast-Hamburg, protokol Bronx,
• MeSH
• Audiometry MeSH
• Child MeSH
• Adult MeSH
• Orthodontic Appliances, Fixed MeSH
• Genetic Diseases, Inborn MeSH
• Genetic Testing MeSH
• Cleidocranial Dysplasia * surgery   diagnosis   therapy   MeSH
• Clinical Protocols MeSH
• Craniofacial Abnormalities MeSH
• Humans MeSH
• Adolescent MeSH
• Orthognathic Surgical Procedures MeSH
• Core Binding Factor Alpha 1 Subunit analysis   MeSH
• Radiography MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Female MeSH

Diamond-like carbon (DLC) is a biocompatible material that has many potential biomedical applications, including in orthopaedics. DLC layers doped with Cr at atomic percent (at.%) of 0, 0.9, 1.8, 7.3, and 7.7 at.% were evaluated with reference to their osteoinductivity with human bone marrow mesenchymal stromal cells (hMSCs), immune activation potential with RAW 264.7 macrophage-like cells, and their effect on apoptosis in Saos-2 human osteoblast-like cells and neonatal human dermal fibroblasts (NHDFs). At mRNA level, hMSCs on DLC doped with 0.9 and 7.7 at.% of Cr reached higher maximum values of both RUNX2 and alkaline phosphatase. An earlier onset of mRNA production of type I collagen and osteocalcin was also observed on these samples; they also supported the production of both type I collagen and osteocalcin. RAW 264.7 macrophages were screened using a RayBio™ Human Cytokine Array for cytokine production. 10 cytokines were at a concentration more than 2 × as high as the concentration of a positive control, but the values for the DLC samples were only moderately higher than the values on glass. NHDF cells, but not Saos-2 cells, had a higher expression of pro-apoptotic markers Bax and Bim and a lower expression of anti-apoptotic factor BCL-XL in proportion to the Cr content. Increased apoptosis was also proven by annexin V staining. These results show that a Cr-doped DLC layer with a lower Cr content can act as an osteoinductive material with relatively low immunogenicity, but that a higher Cr content can induce cell apoptosis.

• MeSH
• Actins metabolism   MeSH
• Alkaline Phosphatase genetics   metabolism   MeSH
• Apoptosis drug effects   immunology   MeSH
• Cell Adhesion drug effects   MeSH
• Cell Differentiation drug effects   immunology   MeSH
• Cell Line MeSH
• Chromium pharmacology   MeSH
• Cytokines metabolism   MeSH
• Diamond pharmacology   MeSH
• Fibroblasts cytology   drug effects   MeSH
• Collagen Type I genetics   metabolism   MeSH
• Humans MeSH
• Macrophages drug effects   metabolism   MeSH
• Mesenchymal Stem Cells cytology   drug effects   immunology   metabolism   MeSH
• Mice MeSH
• Osteogenesis drug effects   MeSH
• Osteocalcin genetics   metabolism   MeSH
• Cell Count MeSH
• Cell Proliferation drug effects   MeSH
• Core Binding Factor Alpha 1 Subunit genetics   metabolism   MeSH
• Gene Expression Regulation drug effects   MeSH
• RNA metabolism   MeSH
• Cell Shape drug effects   MeSH
• Calcium metabolism   MeSH
• Vinculin metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

MiR-21 is being gradually more and more recognized as a molecule regulating bone tissue homeostasis. However, its function is not fully understood due to the dual role of miR-21 on bone-forming and bone-resorbing cells. In this study, we investigated the impact of miR-21 inhibition on pre-osteoblastic cells differentiation and paracrine signaling towards pre-osteoclasts using indirect co-culture model of mouse pre-osteoblast (MC3T3) and pre-osteoclast (4B12) cell lines. The inhibition of miR-21 in MC3T3 cells (MC3T3inh21) modulated expression of genes encoding osteogenic markers including collagen type I (Coll-1), osteocalcin (Ocl), osteopontin (Opn), and runt-related transcription factor 2 (Runx-2). Inhibition of miR-21 in osteogenic cultures of MC3T3 also inflected the synthesis of OPN protein which is essential for proper mineralization of extracellular matrix (ECM) and anchoring osteoclasts to the bones. Furthermore, it was shown that in osteoblasts miR-21 regulates expression of factors that are vital for survival of pre-osteoclast, such as receptor activator of nuclear factor κB ligand (RANKL). The pre-osteoclast cultured with MC3T3inh21 cells was characterized by lowered expression of several markers associated with osteoclasts' differentiation, foremost tartrate-resistant acid phosphatase (Trap) but also receptor activator of nuclear factor-κB ligand (Rank), cathepsin K (Ctsk), carbonic anhydrase II (CaII), and matrix metalloproteinase (Mmp-9). Collectively, our data indicate that the inhibition of miR-21 in MC3T3 cells impairs the differentiation and ECM mineralization as well as influences paracrine signaling leading to decreased viability of pre-osteoclasts.

• MeSH
• Cell Differentiation genetics   MeSH
• Cell Line MeSH
• Extracellular Matrix metabolism   MeSH
• Coculture Techniques MeSH
• Tartrate-Resistant Acid Phosphatase metabolism   MeSH
• RNA, Messenger genetics   MeSH
• MicroRNAs genetics   metabolism   MeSH
• Mice MeSH
• Osteoblasts metabolism   MeSH
• Osteogenesis genetics   MeSH
• Osteoclasts metabolism   MeSH
• Osteopontin genetics   metabolism   MeSH
• Paracrine Communication genetics   MeSH
• Core Binding Factor Alpha 1 Subunit genetics   metabolism   MeSH
• Bone Resorption metabolism   MeSH
• Signal Transduction genetics   MeSH
• Transfection MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10(-5)) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials.

• MeSH
• Adenocarcinoma genetics   pathology   MeSH
• alpha Catenin genetics   MeSH
• Genome-Wide Association Study * MeSH
• Carcinoma, Pancreatic Ductal genetics   pathology   MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• Disease-Free Survival MeSH
• Prognosis MeSH
• Core Binding Factor Alpha 1 Subunit genetics   MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

K osteoporotickým zlomeninám dochází v důsledku změn objemu kostní hmoty a jejího složení a/nebo zhoršené kvality. Ve většině případů je příčinou nerovnováha mezi kostní resorpcí a novotvorbou během remodelačního cyklu. Léčebná intervence zahrnuje buď snížení kostní resorpce (antiresorpční léčba), a/nebo zvýšení novotvorby kosti (anabolická léčba). Léčebné zásahy jsou však komplikovány spřažením mezi kostní resorpcí a novotvorbou během remodelace kosti, což vede k potlačení novotvorby kosti u pacientů léčených antiresorpční léčbou. Pochopení regulačních mechanizmů kostní novotvorby a resorpce přináší nové možnosti léčby osteoporózy. Spektrum nových perspektivních léků je široké – od inovace dosavadních látek se zlepšenými účinky (SERM, kalcitonin), přes ovlivnění metabolizmu osteoklastů (inhibitory katepsinu K, denosumab) a transdukčních dějů v osteoblastech (Wnt signalizace, protilátka proti sklerostinu).

Osteoporotic fractures result from changes in bone mass, architecture and/or quality. In most instances these changes result from an imbalance between bone resorption and formation during the remodeling cycle. Therapeutic intervention can decrease bone resorption (anti-resorptives) and/or increase bone formation (anabolics). These interventions are however complicated by a coupling between resorption and formation in bone remodeling, leading to decreased bone formation in patiens treated with anti-resorptive. The understanding of the regulary mechanisms of the bone formation and the bone resorption brings new options of the treatment of osteoporosis. The range of new promising drugs is wide, from innovation of current agents with enhanced effects (SERM, calcitonin), through modulation of osteoclast metabolism (inhibitors of the cathepsin K, denosumab) and through modulation of transduction procesess in osteoblasts (Wnt signaling, antibodies against sclerostin).

• Keywords
• lasofoxifen, bazedoxifen, sklerostin,
• MeSH
• Diphosphonates pharmacology   MeSH
• Denosumab MeSH
• Calcitonin administration & dosage   pharmacology   MeSH
• Cathepsins antagonists & inhibitors   MeSH
• Humans MeSH
• Antibodies, Monoclonal pharmacology   MeSH
• Osteoporosis drug therapy   physiopathology   MeSH
• Parathyroid Hormone pharmacology   MeSH
• Core Binding Factor Alpha 1 Subunit metabolism   MeSH
• Wnt Proteins metabolism   MeSH
• Raloxifene Hydrochloride pharmacology   MeSH
• Selective Estrogen Receptor Modulators pharmacology   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Review MeSH