Differentiation of mesenchymal stem cells to osteoblasts and chondrocytes: A focus on adenosine receptors
Skeletogenesis, either during development, post-injury or for maintenance, is a carefully coordinated process reliant on the appropriate differentiation of mesenchymal stem cells. Some well described, as well as a new regulator of this process (adenosine receptors), are alike in that they signal via cyclic-AMP (cAMP). This review highlights the known contribution of cAMP signalling to mesenchymal stem cell differentiation to osteoblasts and to chondrocytes. Focus has been given to how these regulators influence the commitment of the osteochondroprogenitor to these separate lineages.
[Show abstract] [Hide abstract] ABSTRACT: Statement of significance: It is well known the importance of biomechanical cues in chondrogenesis. This paper reviews the existing literature on the effect of mechanical stimulation on chondrogenic differentiation of mesenchymal stem cells in order to regenerate hyaline cartilage. Contradictory results found with respect to the effect of different modes of external loading can be explained by the different properties of the scaffolding system that holds the cells, which determine cell adhesion and morphology and spatial distribution of cells, as well as the stress transmission to the cells. Thus, this review seeks to provide an insight into the interplay between external loading program and scaffold properties during chondrogenic differentiation. The review of the literature reveals an important gap in the knowledge in this field and encourages new experimental studies. The main issue is that in each of the few cases in which the interplay is investigated, just two groups of scaffolds are compared, leaving intermediate adhesion conditions out of study. The authors propose broader studies implementing new high-throughput techniques for mechanical characterization of tissue engineering constructs and the inclusion of fatigue analysis as support methodology to more exhaustive mechanical characterization.0Comments 0Citations
- "Receptors from both families have been found to participate in chondrogenic mechanotransduction. It seems that dynamic loading downregulates CD73 (5 0 -nucleotidase), which dephosphorylates cyclic adenosine monophosphate (cAMP) to generate extracellular phosphate and adenosine, as well as the adenosine A2a receptor from the P1 family, leading to chondrogenic differentiation [134,135]. Dynamic loading can also trigger ATP release to the extracellular environment, activating calcium signaling via ATP binding to purine P2 receptors  and chondrogenic differentiation of MSCs. However, the exact mechanisms are not elucidated yet, because ATP release can occur by different routes. "
[Show abstract] [Hide abstract] ABSTRACT: Molecules such as growth factors, peptides and small molecules can guide cellular behavior and are thus important for tissue engineering. They are rapidly emerging as promising compounds for the regeneration of tissues of the musculoskeletal system. Growth factors have disadvantages such as high cost, short half-life, supraphysiological amounts needed, etc. Therefore, small molecules may be an alternative. These molecules have been discovered using high throughput screening. Small osteoinductive molecules exhibit several advantages over growth factors owing to their small sizes, such as high stability and non-immunogenicity. These molecules may stimulate directly signaling pathways that are important for osteogenesis. However, systemic application doesn't induce osteogenesis in most cases. Therefore, local administration is needed. This may be achieved by using a bone graft material providing additional osteoconductive properties. These graft materials can also act by themselves as a delivery matrix for targeted and local delivery. Furthermore, vascularization is necessary in the process of osteogenesis. Many of the small molecules are also capable of promoting vascularization of the tissue to be regenerated. Thus, in this review, special attention is given to molecules that are capable of inducing both angiogenesis and osteogenesis simultaneously. Finally, more recent preclinical and clinical uses in bone regeneration of those molecules are described, highlighting the needs for the clinical translation of these promising compounds. Copyright © 2015. Published by Elsevier B.V.0Comments 2Citations
- "Adenosine can bind all four G proteincoupled receptors commonly found in variety of cell types. Published work can be found for osteogenesis and chondrogenesis  as well as for adipogenesis  stimulation of MSCs using adenosine molecules. In addition, substantial works have demonstrated the link between adenosine signaling and angiogenesis [90,103,106]. "
[Show abstract] [Hide abstract] ABSTRACT: Background Osteoarthritis (OA) is a multi-factorial disease leading progressively to loss of articular cartilage and subsequently to loss of joint function. While hypertrophy of chondrocytes is a physiological process implicated in the longitudinal growth of long bones, hypertrophy-like alterations in chondrocytes play a major role in OA. We performed a quantitative proteomic analysis in osteoarthritic and normal chondrocytes followed by functional analyses to investigate proteome changes and molecular pathways involved in OA pathogenesis. Methods Chondrocytes were isolated from articular cartilage of ten patients with primary OA undergoing knee replacement surgery and six normal donors undergoing fracture repair surgery without history of joint disease and no OA clinical manifestations. We analyzed the proteome of chondrocytes using high resolution mass spectrometry and quantified it by label-free quantification and western blot analysis. We also used WebGestalt, a web-based enrichment tool for the functional annotation and pathway analysis of the differentially synthesized proteins, using the Wikipathways database. ClueGO, a Cytoscape plug-in, is also used to compare groups of proteins and to visualize the functionally organized Gene Ontology (GO) terms and pathways in the form of dynamical network structures. Results The proteomic analysis led to the identification of a total of ~2400 proteins. 269 of them showed differential synthesis levels between the two groups. Using functional annotation, we found that proteins belonging to pathways associated with regulation of the actin cytoskeleton, EGF/EGFR, TGF-β, MAPK signaling, integrin-mediated cell adhesion, and lipid metabolism were significantly enriched in the OA samples (p ≤10−5). We also observed that the proteins GSTP1, PLS3, MYOF, HSD17B12, PRDX2, APCS, PLA2G2A SERPINH1/HSP47 and MVP, show distinct synthesis levels, characteristic for OA or control chondrocytes. Conclusion In this study we compared the quantitative changes in proteins synthesized in osteoarthritic compared to normal chondrocytes. We identified several pathways and proteins to be associated with OA chondrocytes. This study provides evidence for further testing on the molecular mechanism of the disease and also propose proteins as candidate markers of OA chondrocyte phenotype.0Comments 4Citations
- "During OA progression, chondrocytes acquire a hypertrophic phenotype, characterized by altered synthesis of many proteins related to normal development and cartilage turnover. Hypertrophy is a physiological stage in chondrocyte differentiation, and an essential step during bone development [17,18,46,47]. In this study, we showed that hypertrophic osteoarthritic chondrocytes possess a distinct synthesized proteome compared to that of the control group. "