73 research outputs found
PGC-1α in osteoarthritic chondrocytes: From mechanism to target of action
Osteoarthritis (OA) is one of the most common degenerative joint diseases, often involving the entire joint. The degeneration of articular cartilage is an important feature of OA, and there is growing evidence that the mitochondrial biogenesis master regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) exert a chondroprotective effect. PGC-1α delays the development and progression of OA by affecting mitochondrial biogenesis, oxidative stress, mitophagy and mitochondrial DNA (mtDNA) replication in chondrocytes. In addition, PGC-1α can regulate the metabolic abnormalities of OA chondrocytes and inhibit chondrocyte apoptosis. In this paper, we review the regulatory mechanisms of PGC-1α and its effects on OA chondrocytes, and introduce potential drugs and novel nanohybrid for the treatment of OA which act by affecting the activity of PGC-1α. This information will help to further elucidate the pathogenesis of OA and provide new ideas for the development of therapeutic strategies for OA
Ageing in the musculoskeletal system
The extent of ageing in the musculoskeletal system during the life course affects the quality and length of life. Loss of bone, degraded articular cartilage, and degenerate, narrowed intervertebral discs are primary features of an ageing skeleton, and together they contribute to pain and loss of mobility. This review covers the cellular constituents that make up some key components of the musculoskeletal system and summarizes discussion from the 2015 Aarhus Regenerative Orthopaedic Symposium (AROS) (Regeneration in the Ageing Population) about how each particular cell type alters within the ageing skeletal microenvironment
Control of the autophagy pathway in osteoarthritis: key regulators, therapeutic targets and therapeutic strategies
Autophagy is involved in different degenerative diseases and it may control epigenetic modifications, metabolic processes, stem cells differentiation as well as apoptosis. Autophagy plays a key role in maintaining the homeostasis of cartilage, the tissue produced by chondrocytes; its impairment has been associated to cartilage dysfunctions such as osteoarthritis (OA). Due to their location in a reduced oxygen context, both differentiating and mature chondrocytes are at risk of premature apoptosis, which can be prevented by autophagy. AutophagomiRNAs, which regulate the autophagic process, have been found differentially expressed in OA. AutophagomiRNAs, as well as other regulatory molecules, may also be useful as therapeutic targets. In this review, we describe and discuss the role of autophagy in OA focusing mainly on the control of autophagomiRNAs in OA pathogenesis and on their potential therapeutic applications
Insulin/IGF-1R, SIRT1, and FOXOs PathwaysâAn Intriguing Interaction Platform for Bone and Osteosarcoma
Aging is a substantial risk factor for the development of osteoarthritis (OA) and, probably, an essential substrate for the development of neoplastic disease of the bone, such as osteosarcoma, which is the most common malignant mesenchymal primary bone tumor. Genetic studies have established that the insulin/insulin-like growth factor 1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT (Protein Kinase B) signal transduction pathway is involved across species, including nematodes, fruit flies, and mammals. SIRT1, a phylogenetically-conserved family of deacetylases, seems to play pleiotropic effects in epithelial malignancies of the liver and interact with the IGF-1/PI3K/AKT signal transduction pathway. Some of the most critical processes in degenerative conditions may indeed include the insulin/IGF1R and SIRT1 signaling pathways as well as some specific transcription factors. The Forkhead box O (FOXO) transcription factors (FOXOs) control diverse cellular functions, such as metabolism, longevity, and cell death. FOXOs play a critical role in the IGF-1/PI3K/AKT signal transduction pathway. FOXOs can indeed be modulated to reduce age-related diseases. FOXOs have advantageous inhibitory effects on fibroblast and myofibroblast activation, which are accompanied by a subsequent excessive production of extracellular matrix. FOXOs can block or decrease the fibrosis levels in numerous organs. Previously, we observed a correlation between nuclear FOXO3 and high caspase-8 expression, which induces cellular apoptosis in response to harmful external stimuli. In this perspective, we emphasize the current advances and interactions involving the insulin/IGF1R, SIRT1, and FOXOs pathways in the bone and osteosarcoma for a better understanding of the mechanisms potentially underpinning tissue degeneration and tumorigenesis
The Role of FoxO Transcription Factors in Alcohol-Induced Deficient Fracture Repair
Proper and complete repair of a bone fracture is essential in quality of life maintenance, but poor healing and fracture malunion are still medically and socially relevant problems. Alcohol abuse impairs normal fracture healing, leading to delayed or incomplete union. This dissertation aims to clarify mechanisms behind this alcohol-induced impaired healing, thereby elucidating potential methods of intervention.
Alcohol-induced oxidative stress has been linked to many morbidities associated with alcohol abuse. This dissertation elucidates a potential mechanism through which alcohol inhibits fracture healing by increasing oxidative stress. Using a rodent model, I found that alcohol exposure decreases fracture callus formation and endochondral ossification, and these changes are associated with markers of activation of FoxO transcription factors. FoxO transcription factors are known to be activated by oxidative stress and inhibit proper mesenchymal stem cell differentiation, which is crucial in callus formation. These deleterious effects of alcohol were prevented with the administration of an antioxidant. These results begin to illuminate how alcohol abuse can negatively affect fracture healing and bone health in general, while characterizing aspects of skeletal biology that are applicable beyond alcohol-associated pathologies
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Novel intracellular signalling regulators of cartilage progenitor cell populations
Cartilage is a viscoelastic tissue that absorbs shocks and facilitates low friction of the joint. Adult articular cartilage is limited in its ability to self-repair. Lesions or gradual wear-and-tear affect cartilage integrity and lead to damage that, when untreated, can ultimately develop to osteoarthritis. Osteoarthritis is a considerable health burden and is a leading cause of disability worldwide. In order to address this burdensome condition, several treatments have been developed. In particular, therapies that allow delivery of bone marrow and its constituent cell populations to the site of cartilage damage to form a regenerative clot have proved promising in repairing joint cartilage defects. In order to improve such regenerative technique, further research is required to provide a deeper understanding of the mechanisms underlying cartilage regeneration. One of the critical players are the cells that originally reside in the cartilage surrounding the damage. How these resident cells contribute to the activity of cells within the repair tissue at the site of cartilage damage is largely undescribed.
In this thesis chondrocytes from three different cartilage areas were compared: chondrocytes from 1) the superficial (SZ) and 2) the middle-deep (MDZ) zone of non-weight bearing femoral condyles, and from 3) the osteoarthritic zone (OAZ) of patients undergoing knee replacement. More inflammatory factors and cytokines are present in MSCs co-culture with OA cartilage chips, and with MDZ cartilage chips. To assess how chondrocyte-MSC crosstalk would affect MSCs chondrogenesis, cartilage chips from the three different zones were co-cultured with BMSC pellets. Results indicated that the SZ induce chondrogenic differentiation of BMSCs, whereas MDZ and OAZ have a negative effect, compared to control conditions. The findings suggest that the presence of SZ, which has been reported to reduce with age, is important to direct BMSCs differentiation towards the chondrogenic fate.
In order to better understand the molecular mechanism that differentiate SZ from MDZ and OA chondrocytes, DACTs (Dapper antagonist of catenin) were studied. DACT1 and DACT2 are known to be Wnt and TGFÎČ pathways regulators, but their role in chondrocytes and MSCs has not been described before. Both proteins are present in chondrocytes throughout the osteoarthritic human tissue, including in chondrocytes forming cell clusters. On the non-weight bearing and visually undamaged cartilage, DACT1 and DACT2 expression is localised to the articular surface. In mouse embryos (E.15.5), DACT2 is expressed at the interzone, site of developing synovial joint, indicating that DACT2 is expressed in cells that give rise to the articular joint. Subsequently the expression of DACT1 and DACT2 was analysed in MSCs: both are expressed in synovial and bone marrow-derived MSCs. Following this observation an RNAi knockdown experiment showed that DACT1 knockdown in both chondrocyte and MSCs causes the cells to undergo apoptosis within 24 hours. To understand the pathway regulated by DACT1, next generation sequencing gene expression analysis was performed on BMSCs where DACT1 had been reduced by RNAi. The study showed that loss of DACT1 influences the expression (p<0.05) of genes involved in both TGFÎČ and Wnt pathways and putative link to relevant cell regulatory pathways (IngenuityÂź Pathway Analysis). SMURF2 and other genes involved in protein phosphorylation and degradation are downregulated following DACT1 knockdown. This suggests that DACT1 is an upstream regulator of SMAD protein phosphorylation affecting proliferation and survival of MSCs.
The data presented in this thesis has indicated that different types of chondrocytes are present within human articular cartilage and that they cross talk with MSCs differently according to their regional origin. This information offers a new level of complexity to consider to improve regenerative techniques. In addition, this work describes for the first time, the presence and biological relevance of DACT1 and DACT2 in chondrocytes and MSCs. DACT1 is involved in MSCs survival and is downregulated in OA which suggest that this is an important regulatory protein. Further studies of DACT1 could help elucidate mechanisms involved in OA, but also uncover the relevance of cartilage progenitors loss in the development of cartilage degeneration
Ginsenosides on stem cells fate specificationâa novel perspective
Recent studies have demonstrated that stem cells have attracted much attention due to their special abilities of proliferation, differentiation and self-renewal, and are of great significance in regenerative medicine and anti-aging research. Hence, finding natural medicines that intervene the fate specification of stem cells has become a priority. Ginsenosides, the key components of natural botanical ginseng, have been extensively studied for versatile effects, such as regulating stem cells function and resisting aging. This review aims to summarize recent progression regarding the impact of ginsenosides on the behavior of adult stem cells, particularly from the perspective of proliferation, differentiation and self-renewal
Osteoarthritis in the Elderly Population: Preclinical Evidence of Nutrigenomic Activities of Flavonoids
Osteoarthritis (OA) is a degenerative joint disease that is age-related and progressive. It causes the destruction of articular cartilage and underlying bone, often aggravated by inflammatory processes and oxidative stresses. This pathology impairs the quality of life of the elderly, causing pain, reduced mobility, and functional disabilities, especially in obese patients. Phytochemicals with anti-inflammatory and antioxidant activities may be used for long-term treatment of OA, either in combination with current anti-inflammatories and painkillers, or as an alternative to other products such as glucosamine and chondroitin, which improve cartilage structure and elasticity. The current systematic review provides a comprehensive understanding of the use of flavonoids. It highlights chondrocyte, cartilage, and subchondral bone activities, with a particular focus on their nutrigenomic effects. The molecular mechanisms of these molecules demonstrate how they can be used for the prevention and treatment of OA in the elderly population. However, clinical trials are still needed for effective use in clinical practice
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