Low back pain (LBP), frequently associated with intervertebral disc (IVD) degeneration, is a major public health concern. LBP is currently managed by pharmacological treatments and, if unsuccessful, ...by invasive surgical procedures, which do not counteract the degenerative process.
Considering that IVD cell depletion is critical in the degenerative process, the supplementation of IVD with reparative cells, associated or not with biomaterials, has been contemplated. Recently, the discovery of reparative stem/progenitor cells in the IVD has led to increased interest in the potential of endogenous repair strategies. Recruitment of these cells by specific signals might constitute an alternative strategy to cell transplantation. Here, we review the status of cell-based therapies for treating IVD degeneration and emphasize the current concept of endogenous repair as well as future perspectives. This review also highlights the challenges of the mobilization/differentiation of reparative progenitor cells through the delivery of biologics factors to stimulate IVD regeneration.
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Inorganic phosphate (Pi) and the matrix Gla protein (MGP) are key regulators of bone formation. We have recently shown that Pi upregulates MGP in growth plate chondrocytes, which may represent a ...negative feedback loop for the control of mineralization. Osteoblasts from Fra‐1‐deleted mice express low levels of MGP, whereas the expression of MGP is elevated in Fra‐1 transgenic osteoblasts, suggesting a role for Fra‐1 in MGP expression and bone formation. In this study, we aimed at deciphering the relationships between Pi and MGP in osteoblasts to determine the molecular mechanisms involved in the Pi‐dependent regulation of MGP. In MC3T3‐E1 cells and primary calvaria‐derived osteoblasts, Pi increased MGP and Fra‐1 expression at both the mRNA and protein levels. We also found that Pi enhanced the phosphorylation of ERK1/2. U0126 (MEK1/2 inhibitor) suppressed Pi‐stimulated MGP and Fra‐1 expression, indicating that ERK1/2 is required for Pi‐dependent regulation of MGP and Fra‐1. In addition, using in vitro DNA binding and chromatin immunoprecipitation assays, we showed that Fra‐1 interacts with the MGP promoter in response to Pi in MC3T3‐E1 cells. Finally, we found that in fra‐1 knockdown MC3T3‐E1 osteoblasts, the level of MGP expression is no more significantly upregulated by Pi. We further showed that primary osteoblasts from Fra‐1‐deficient mice failed to exhibit a Pi‐dependent stimulation of MGP expression. These data show, for the first time, that Pi regulates MGP expression in osteoblasts through the ERK1/2‐Fra‐1 pathway.
Intervertebral disc (IVD) degeneration has been associated with low back pain, which is a major musculoskeletal disorder and socio-economic problem that affects as many as 600 million patients ...worldwide. Here, we first review the current knowledge of IVD physiology and physiopathological processes in terms of homeostasis regulation and consecutive events that lead to tissue degeneration. Recent progress with IVD restoration by anti-catabolic or pro-anabolic approaches are then analyzed, as are the design of macro-, micro-, and nano-platforms to control the delivery of such therapeutic agents. Finally, we hypothesize that a sequential delivery strategy that i) firstly targets the inflammatory, pro-catabolic microenvironment with release of anti-inflammatory or anti-catabolic cytokines; ii) secondly increases cell density in the less hostile microenvironment by endogenous cell recruitment or exogenous cell injection, and finally iii) enhances cellular synthesis of extracellular matrix with release of pro-anabolic factors, would constitute an innovative yet challenging approach to IVD regeneration.
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Osteoarthritis is an age-related disease that currently faces a lack of symptomatic treatment. Inflammation, which is mainly sustained by pro-inflammatory cytokines such as IL-1b, TNF, and IL-6, ...plays an important role in osteoarthritis progression. In this context, pro-inflammatory cytokines are widely used to mimic the inflammatory component of osteoarthritis in vitro. However, the therapeutic failures of clinical trials evaluating anti-cytokines drugs highlight the lack of overall understanding of the effects of these cytokines on chondrocytes.
Here, we generated a comprehensive transcriptomic and proteomic dataset of osteoarthritic chondrocytes treated with these cytokines to describe their pro-inflammatory signature and compare it to the transcriptome of non-osteoarthritic chondrocytes. Then, the dysregulations highlighted at the molecular level were functionally confirmed by real-time cellular metabolic assays.
We identified dysregulation of metabolic-related genes in osteoarthritic chondrocytes but not in non-osteoarthritic chondrocytes. A metabolic shift, toward increased glycolysis at the expense of mitochondrial respiration, was specifically confirmed in osteoarthritic chondrocytes treated with IL-1b or TNF.
These data show a strong and specific association between inflammation and metabolism in osteoarthritic chondrocytes, which was not found in non-osteoarthritic chondrocytes. This indicates that the link between inflammation and metabolic dysregulation may be exacerbated during chondrocyte damage in osteoarthritis. Video Abstract.
Osteoarthritis is the most common musculoskeletal disease causing chronic disability in adults. Studying cartilage aging, chondrocyte senescence, inflammation, and autophagy mechanisms have ...identified promising targets and pathways with clinical translatability potential. In this review, we highlight the most recent mechanistic and therapeutic preclinical models of aging with particular relevance in the context of articular cartilage and OA. Evidence supporting the role of metabolism, nuclear receptors and transcription factors, cell senescence, and circadian rhythms in the development of musculoskeletal system degeneration assure further translational efforts. This information might be useful not only to propose hypothesis and advanced models to study the molecular mechanisms underlying joint degeneration, but also to translate our knowledge into novel disease-modifying therapies for OA.
Abstract An injectable hydrogel, acting as a reservoir for cell delivery and mimicking the native environment, offers promise for nucleus pulposus (NP) repair and regeneration. Herein, the potential ...of a stabilised type II collagen hydrogel using poly(ethylene glycol) ether tetrasuccinimidyl glutarate (4S-StarPEG) cross-linker, enriched with hyaluronic acid (HA) was investigated. The optimally stabilised type II collagen hydrogel was determined by assessing free amine groups, resistance to enzymatic degradation, gel point. The potential toxicity of the cross-linker was initially assessed against adipose-derived stem cells (ADSCs). After addition of HA (molar ratio type II collagen:HA 9:0, 9:1, 9:4.5, 9:9) within the hydrogel, the behaviour of the encapsulated NP cells was evaluated using cell proliferation assay, gene expression analysis, cell distribution and cell morphology. A significant decrease ( p < 0.05) in the free amine groups of collagen was observed, confirming successful cross-linking. Gelation was independent of the concentration of 4S-StarPEG (8 min at 37 °C). The 1 m m cross-linked hydrogel yielded the most stable after enzymatic degradation ( p < 0.05). No toxicity of the 4S-StarPEG was noted for the ADSCs. NP cell viability was high regardless of the concentration of HA (>80%). A cell proliferation was not seen after 14 days in its presence. At a gene expression level, HA did not influence NP cells phenotype after seven days in culture. After seven days in culture, the type I collagen mRNA expression was maintained ( p > 0.05). The optimally stabilised and functionalised type II collagen/HA hydrogel system developed in this study shows promise as an injectable reservoir system for intervertebral disc regeneration.
Injuries to articular cartilage are one of the most challenging issues of musculoskeletal medicine due to the poor intrinsic ability of this tissue for repair. The lack of efficient modalities of ...treatment has prompted research into tissue engineering combining chondrogenic cells, scaffold materials and environmental factors. The aim of this review is to focus on the recent advances made in exploiting the potential of biomaterial-assisted cell therapy for cartilage engineering. We discuss the requirements for identifying additional specific growth factors and evaluating the optimal combination of cells, growth factors and scaffolds that is able to respond to the functional demand placed upon cartilage tissue replacement in clinics. Finally, some of the major obstacles encountered in cartilage engineering are discussed, as well as future trends in clinical applications.
Boronate ester (BE) hydrogels are increasingly used for biomedical applications. The dynamic nature of these molecular networks enables bond rearrangement, which is associated with viscoelasticity, ...injectability, printability, and self-healing, among other properties. BEs are also sensitive to pH, redox reactions, and the presence of sugars, which is useful for the design of stimuli-responsive materials. Together, BE hydrogels are interesting scaffolds for use in drug delivery, 3D cell culture, and biofabrication. However, designing stable BE hydrogels at physiological pH (≈7.4) remains a challenge, which is hindering their development and biomedical application. In this context, advanced chemical insights into BE chemistry are being used to design new molecular solutions for material fabrication. This review article summarizes the state of the art in BE hydrogel design for biomedical applications with a focus on the materials chemistry of this class of materials. First, we discuss updated knowledge in BE chemistry including details on the molecular mechanisms associated with BE formation and breakage. Then, we discuss BE hydrogel formation at physiological pH, with an overview of the main systems reported to date along with new perspectives. A last section covers several prominent biomedical applications of BE hydrogels, including drug delivery, 3D cell culture, and bioprinting, with critical insights on the design relevance, limitations and potential.
Repairing or replacing damaged human tissues has been the ambitious goal of regenerative medicine for over 25years. One promising approach is the use of hydrated three-dimensional scaffolds, known as ...hydrogels, which have had good results repairing tissues in pre-clinical trials. Benefiting from breakthrough advances in the field of biology, and more particularly regarding cell/matrix interactions, these hydrogels are now designed to recapitulate some of the fundamental cues of native environments to drive the local tissue regeneration. We highlight the key parameters that are required for the development of smart and biomimetic hydrogels. We also review the wide variety of polymers, crosslinking methods, and manufacturing processes that have been developed over the years. Of particular interest is the emergence of supramolecular chemistries, allowing for the development of highly functional and reversible biohydrogels. Moreover, advances in computer assisted design and three-dimensional printing have revolutionized the production of macroporous hydrogels and allowed for more complex designs than ever before with the opportunity to develop fully reconstituted organs. Today, the field of biohydrogels for regenerative medicine is a prolific area of research with applications for most bodily tissues. On top of these applications, injectable hydrogels and macroporous hydrogels (foams) were found to be the most successful. While commonly associated with cells or biologics as drug delivery systems to increase therapeutic outcomes, they are steadily being used in the emerging fields of organs-on-chip and hydrogel-assisted cell therapy. To highlight these advances, we review some of the recent developments that have been achieved for the regeneration of tissues, focusing on the articular cartilage, bone, cardiac, and neural tissues. These biohydrogels are associated with improved cartilage and bone defects regeneration, reduced left ventricular dilation upon myocardial infarction and display promising results repairing neural lesions. Combining the benefits from each of these areas reviewed above, we envision that an injectable biohydrogel foam loaded with either stem cells or their secretome is the most promising hydrogel solution to trigger tissue regeneration. A paradigm shift is occurring where the combined efforts of fundamental and applied sciences head toward the development of hydrogels restoring tissue functions, serving as drug screening platforms or recreating complex organs.
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•Biohydrogels are 3D scaffolds designed for the field of regenerative medicine.•Hydrogels are increasingly used to study cell/matrix interactions.•Hydrogels can incorporate cells and/or biologics to improve therapeutic outcomes.•Injectable hydrogels and foams are increasingly used for clinical applications.•Injectable biohydrogel foams offer unequalled handling and biological properties.
Oxidative stress is characterised by an increased level of reactive oxygen species (ROS) that disrupts the intracellular reduction–oxidation (redox) balance. Although initially shown to be involved ...in aging, physiological roles for ROS in regulating cell functions and mediating intracellular signals have emerged. In bone tissues, recent studies have demonstrated that ROS generation is a key modulator of bone cell function and that oxidative status influences the pathophysiology of mineralised tissues. Here, we review the crucial role of oxidative stress in bone pathophysiology, and discuss the possibility that ROS production might be a relevant therapeutic target under certain conditions. Further studies will be needed to investigate whether manipulation of the redox balance in bone cells represents a useful approach in the design of future therapies for bone diseases.
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