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International Journal of Molecular... Mar 2020Osteoarthritis (OA) is the most common joint disease that causes pain and disability in the adult population. OA is primarily caused by trauma induced by an external... (Review)
Review
Osteoarthritis (OA) is the most common joint disease that causes pain and disability in the adult population. OA is primarily caused by trauma induced by an external force or by age-related cartilage damage. Chondrocyte hypertrophy or chondrocyte senescence is thought to play a role in the initiation and progression of OA. Although chondrocyte hypertrophy and cell death are both crucial steps during the natural process of endochondral bone formation, the abnormal activation of these two processes after injury or during aging seems to accelerate the progression of OA. However, the exact mechanisms of OA progression and these two processes remain poorly understood. Chondrocyte senescence and hypertrophy during OA share various markers and processes. In this study, we reviewed the changes that occur during chondrocyte hypertrophy or senescence in OA and the attempts that were made to regulate them. Regulation of hypertrophic or senescent chondrocytes might be a potential therapeutic target to slow down or stop OA progression; thus, a better understanding of the processes is required for management.
Topics: Animals; Biomarkers; Cartilage, Articular; Cell Differentiation; Cell Proliferation; Cellular Senescence; Chondrocytes; Chondrogenesis; Disease Progression; Disease Susceptibility; Gene Expression Regulation; Humans; Hypertrophy; Osteoarthritis; Osteogenesis; Signal Transduction
PubMed: 32235300
DOI: 10.3390/ijms21072358 -
Cold Spring Harbor Perspectives in... Jan 2013Much of the mammalian skeleton is composed of bones that originate from cartilage templates through endochondral ossification. Elucidating the mechanisms that control... (Review)
Review
Much of the mammalian skeleton is composed of bones that originate from cartilage templates through endochondral ossification. Elucidating the mechanisms that control endochondral bone development is critical for understanding human skeletal diseases, injury response, and aging. Mouse genetic studies in the past 15 years have provided unprecedented insights about molecules regulating chondrocyte formation, chondrocyte maturation, and osteoblast differentiation, all key processes of endochondral bone development. These include the roles of the secreted proteins IHH, PTHrP, BMPs, WNTs, and FGFs, their receptors, and transcription factors such as SOX9, RUNX2, and OSX, in regulating chondrocyte and osteoblast biology. This review aims to integrate the known functions of extracellular signals and transcription factors that regulate development of the endochondral skeleton.
Topics: Animals; Cell Differentiation; Chondrocytes; Gene Expression Regulation, Developmental; Growth Plate; Humans; Mice; Models, Biological; Models, Genetic; Osteoblasts; Osteogenesis; Signal Transduction; Transcription Factors
PubMed: 23284041
DOI: 10.1101/cshperspect.a008334 -
International Journal of Molecular... Aug 2015Cell death with morphological and molecular features of apoptosis has been detected in osteoarthritic (OA) cartilage, which suggests a key role for chondrocyte... (Meta-Analysis)
Meta-Analysis Review
Cell death with morphological and molecular features of apoptosis has been detected in osteoarthritic (OA) cartilage, which suggests a key role for chondrocyte death/survival in the pathogenesis of OA. Identification of biomarkers of chondrocyte apoptosis may facilitate the development of novel therapies that may eliminate the cause or, at least, slow down the degenerative processes in OA. The aim of this review was to explore the molecular markers and signals that induce chondrocyte apoptosis in OA. A literature search was conducted in PubMed, Scopus, Web of Science and Google Scholar using the keywords chondrocyte death, apoptosis, osteoarthritis, autophagy and biomarker. Several molecules considered to be markers of chondrocyte apoptosis will be discussed in this brief review. Molecular markers and signalling pathways associated with chondroycte apoptosis may turn out to be therapeutic targets in OA and approaches aimed at neutralizing apoptosis-inducing molecules may at least delay the progression of cartilage degeneration in OA.
Topics: Animals; Apoptosis; Autophagy; Biomarkers; Chondrocytes; Humans; Osteoarthritis; Signal Transduction
PubMed: 26334269
DOI: 10.3390/ijms160920560 -
International Journal of Molecular... Oct 2015Apoptosis is a highly-regulated, active process of cell death involved in development, homeostasis and aging. Dysregulation of apoptosis leads to pathological states,... (Review)
Review
Apoptosis is a highly-regulated, active process of cell death involved in development, homeostasis and aging. Dysregulation of apoptosis leads to pathological states, such as cancer, developmental anomalies and degenerative diseases. Osteoarthritis (OA), the most common chronic joint disease in the elderly population, is characterized by progressive destruction of articular cartilage, resulting in significant disability. Because articular cartilage depends solely on its resident cells, the chondrocytes, for the maintenance of extracellular matrix, the compromising of chondrocyte function and survival would lead to the failure of the articular cartilage. The role of subchondral bone in the maintenance of proper cartilage matrix has been suggested as well, and it has been proposed that both articular cartilage and subchondral bone interact with each other in the maintenance of articular integrity and physiology. Some investigators include both articular cartilage and subchondral bone as targets for repairing joint degeneration. In late-stage OA, the cartilage becomes hypocellular, often accompanied by lacunar emptying, which has been considered as evidence that chondrocyte death is a central feature in OA progression. Apoptosis clearly occurs in osteoarthritic cartilage; however, the relative contribution of chondrocyte apoptosis in the pathogenesis of OA is difficult to evaluate, and contradictory reports exist on the rate of apoptotic chondrocytes in osteoarthritic cartilage. It is not clear whether chondrocyte apoptosis is the inducer of cartilage degeneration or a byproduct of cartilage destruction. Chondrocyte death and matrix loss may form a vicious cycle, with the progression of one aggravating the other, and the literature reveals that there is a definite correlation between the degree of cartilage damage and chondrocyte apoptosis. Because current treatments for OA act only on symptoms and do not prevent or cure OA, chondrocyte apoptosis would be a valid target to modulate cartilage degeneration.
Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Biomarkers; Chondrocytes; Humans; Mitochondria; Molecular Targeted Therapy; Osteoarthritis; Signal Transduction
PubMed: 26528972
DOI: 10.3390/ijms161125943 -
Developmental Cell Jun 2020Correct functioning of chondrocytes is crucial for long bone growth and fracture repair. These cells are highly anabolic but survive and function in an avascular...
Correct functioning of chondrocytes is crucial for long bone growth and fracture repair. These cells are highly anabolic but survive and function in an avascular environment, implying specific metabolic requirements that are, however, poorly characterized. Here, we show that chondrocyte identity and function are closely linked with glutamine metabolism in a feedforward process. The master chondrogenic transcription factor SOX9 stimulates glutamine metabolism by increasing glutamine consumption and levels of glutaminase 1 (GLS1), a rate-controlling enzyme in this pathway. Consecutively, GLS1 action is critical for chondrocyte properties and function via a tripartite mechanism. First, glutamine controls chondrogenic gene expression epigenetically through glutamate dehydrogenase-dependent acetyl-CoA synthesis, necessary for histone acetylation. Second, transaminase-mediated aspartate synthesis supports chondrocyte proliferation and matrix synthesis. Third, glutamine-derived glutathione synthesis avoids harmful reactive oxygen species accumulation and allows chondrocyte survival in the avascular growth plate. Collectively, our study identifies glutamine as a metabolic regulator of cartilage fitness during bone development.
Topics: Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; Chondrocytes; Female; Glutaminase; Glutamine; Male; Mice; SOX9 Transcription Factor
PubMed: 32470321
DOI: 10.1016/j.devcel.2020.05.001 -
Development (Cambridge, England) Mar 2015Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from... (Review)
Review
Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from mesenchymal progenitor cells to their terminal maturation into hypertrophic chondrocytes. Here, we review how multiple signaling molecules, mechanical signals and morphological cell features are integrated to activate a set of key transcription factors that determine and regulate the genetic program that induces chondrogenesis and chondrocyte differentiation. Moreover, we describe recent findings regarding the roles of several signaling pathways in modulating the proliferation and maturation of chondrocytes in the growth plate, which is the 'engine' of bone elongation.
Topics: Animals; Chondrocytes; Chondrogenesis; Growth Plate; Humans; Transcription Factors
PubMed: 25715393
DOI: 10.1242/dev.105536 -
ELife Apr 2023The progenitor cells that form articular cartilage express a gene for a protein called NFATc1, which stops articular chondrocytes from developing too early in the joint.
The progenitor cells that form articular cartilage express a gene for a protein called NFATc1, which stops articular chondrocytes from developing too early in the joint.
Topics: Cell Differentiation; Chondrocytes; Cartilage, Articular; Stem Cells
PubMed: 37017508
DOI: 10.7554/eLife.87355 -
Cells Dec 2022Autologous chondrocyte implantation (ACI) is a cell therapy to repair cartilage defects. In ACI a biopsy is taken from a non-load bearing area of the knee and expanded... (Review)
Review
Autologous chondrocyte implantation (ACI) is a cell therapy to repair cartilage defects. In ACI a biopsy is taken from a non-load bearing area of the knee and expanded in-vitro. The expansion process provides the benefit of generating a large number of cells required for implantation; however, during the expansion these cells de-differentiate and lose their chondrocyte phenotype. In this review we focus on examining the de-differentiation phenotype from a mechanobiology and biophysical perspective, highlighting some of the nuclear mechanics and chromatin changes in chondrocytes seen during the expansion process and how this relates to the gene expression profile. We propose that manipulating chondrocyte nuclear architecture and chromatin organization will highlight mechanisms that will help to preserve the chondrocyte phenotype.
Topics: Chondrocytes; Cues; Cell Differentiation; Knee Joint; Phenotype
PubMed: 36552775
DOI: 10.3390/cells11244011 -
Connective Tissue Research Jan 2017SOX9 is a pivotal transcription factor in developing and adult cartilage. Its gene is expressed from the multipotent skeletal progenitor stage and is active throughout... (Review)
Review
SOX9 is a pivotal transcription factor in developing and adult cartilage. Its gene is expressed from the multipotent skeletal progenitor stage and is active throughout chondrocyte differentiation. While it is repressed in hypertrophic chondrocytes in cartilage growth plates, it remains expressed throughout life in permanent chondrocytes of healthy articular cartilage. SOX9 is required for chondrogenesis: it secures chondrocyte lineage commitment, promotes cell survival, and transcriptionally activates the genes for many cartilage-specific structural components and regulatory factors. Since heterozygous mutations within and around SOX9 were shown to cause the severe skeletal malformation syndrome called campomelic dysplasia, researchers around the world have worked assiduously to decipher the many facets of SOX9 actions and regulation in chondrogenesis. The more we learn, the more we realize the complexity of the molecular networks in which SOX9 fulfills its functions and is regulated at the levels of its gene, RNA, and protein, and the more we measure the many gaps remaining in knowledge. At the same time, new technologies keep giving us more means to push further the frontiers of knowledge. Research efforts must be pursued to fill these gaps and to better understand and treat many types of cartilage diseases in which SOX9 has or could have a critical role. These diseases include chondrodysplasias and cartilage degeneration diseases, namely osteoarthritis, a prevalent and still incurable joint disease. We here review the current state of knowledge of SOX9 actions and regulation in the chondrocyte lineage, and propose new directions for future fundamental and translational research projects.
Topics: Animals; Campomelic Dysplasia; Cell Differentiation; Chondrocytes; Chondrogenesis; Gene Expression Regulation; Humans; SOX9 Transcription Factor; Transcription, Genetic
PubMed: 27128146
DOI: 10.1080/03008207.2016.1183667 -
International Journal of Molecular... Jun 2020Chondrocyte biology is a hot topic, because osteoarthritis (OA) is a serious problem in an aging society, but there are no fundamental therapeutic drugs [...].
Chondrocyte biology is a hot topic, because osteoarthritis (OA) is a serious problem in an aging society, but there are no fundamental therapeutic drugs [...].
Topics: Animals; Chondrocytes; Gene Expression Regulation; Humans; Osteoarthritis; Osteochondrosis
PubMed: 32545161
DOI: 10.3390/ijms21114161