Review

Authors: Fanxin Long, David M Ornitz

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

Meta-Analysis Review

Authors: Giuseppe Musumeci, Paola Castrogiovanni, Francesca Maria Trovato...

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

Review

Authors: Hyun Sook Hwang, Hyun Ah Kim

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

Authors: Steve Stegen, Gianmarco Rinaldi, Shauni Loopmans...

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

Review

Authors: Elena Kozhemyakina, Andrew B Lassar, Elazar Zelzer...

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

Authors: Nana Geng, Mengtian Fan, Biao Kuang...

Osteoarthritis is a degenerative joint disease with joint pain as the main symptom, caused by fibrosis and loss of articular cartilage. Due to the complexity and heterogeneity of osteoarthritis, there is a lack of effective individualized disease-modifying osteoarthritis drugs in clinical practice. Chondrocyte senescence is reported to participate in occurrence and progression of osteoarthritis. Here we show that small molecule 10-hydroxy-2-decenoic acid suppresses cartilage degeneration and relieves pain in the chondrocytes, cartilage explants from osteoarthritis patients, surgery-induced medial meniscus destabilization or naturally aged male mice. We further confirm that 10-hydroxy-2-decenoic acid exerts a protective effect by targeting the glycosylation site in the Asp_Arg_Hydrox domain of aspartyl β-hydroxylase. Mechanistically, 10-hydroxy-2-decenoic acid alleviate cellular senescence through the ERK/p53/p21 and GSK3β/p16 pathways in the chondrocytes. Our study uncovers that 10-hydroxy-2-decenoic acid modulate cartilage metabolism by targeting aspartyl β-hydroxylase to inhibit chondrocyte senescence in osteoarthritis. 10-hydroxy-2-decenoic acid may be a promising therapeutic drug against osteoarthritis.

Topics: Animals; Chondrocytes; Male; Osteoarthritis; Mice; Cellular Senescence; Humans; Fatty Acids, Monounsaturated; Cartilage, Articular; Mice, Inbred C57BL; Disease Models, Animal; Female

PubMed: 39231947
DOI: 10.1038/s41467-024-51746-3

Authors: Jiahui Hou, Yanpeng Lin, Chencheng Zhu...

Chondrocyte senescence and reduced lubrication play pivotal roles in the pathogenesis of age-related osteoarthritis (OA). In the present study, highly lubricated and drug-loaded hydrogel microspheres are designed and fabricated through the radical polymerization of sulfobetaine (SB)-modified hyaluronic acid methacrylate using microfluidic technology. The copolymer contains a large number of SB and carboxyl groups that can provide a high degree of lubrication through hydration and form electrostatic loading interactions with metformin (Met@SBHA), producing a high drug load for anti-chondrocyte senescence. Mechanical, tribological, and drug release analyses demonstrated enhanced lubricative properties and prolonged drug dissemination of the Met@SBHA microspheres. RNA sequencing (RNA-seq) analysis, network pharmacology, and in vitro assays revealed the extraordinary capacity of Met@SBHA to combat chondrocyte senescence. Additionally, inducible nitric oxide synthase (iNOS) has been identified as a promising protein modulated by Met in senescent chondrocytes, thereby exerting a significant influence on the iNOS/ONOO-/P53 pathway. Notably, the intra-articular administration of Met@SBHA in aged mice ameliorated cartilage senescence and OA pathogenesis. Based on the findings of this study, Met@SBHA emerges as an innovative and promising strategy in tackling age-related OA serving the dual function of enhancing joint lubrication and mitigating cartilage senescence.

Topics: Metformin; Animals; Mice; Osteoarthritis; Microspheres; Hydrogels; Disease Models, Animal; Chondrocytes; Cellular Senescence

PubMed: 38874373
DOI: 10.1002/advs.202402477

Review

Authors: Miradj Siddick Adam, Huangming Zhuang, Xunshan Ren...

Osteoarthritis (OA) is an intricate pathological condition that primarily affects the entire synovial joint, especially the hip, hand, and knee joints. This results in inflammation in the synovium and osteochondral injuries, ultimately causing functional limitations and joint dysfunction. The key mechanism responsible for maintaining articular cartilage function is chondrocyte metabolism, which involves energy generation through glycolysis, oxidative phosphorylation, and other metabolic pathways. Some studies have shown that chondrocytes in OA exhibit increased glycolytic activity, leading to elevated lactate production and decreased cartilage matrix synthesis. In OA cartilage, chondrocytes display alterations in mitochondrial activity, such as decreased ATP generation and increased oxidative stress, which can contribute to cartilage deterioration. Chondrocyte metabolism also involves anabolic processes for extracellular matrix substrate production and energy generation. During OA, chondrocytes undergo considerable metabolic changes in different aspects, leading to articular cartilage homeostasis deterioration. Numerous studies have been carried out to provide tangible therapies for OA by using various models and targeting chondrocyte metabolism, although there are still certain limitations. With growing evidence indicating the essential role of chondrocyte metabolism in disease etiology, this literature review explores the metabolic characteristics and changes of chondrocytes in the presence of OA, both and . To provide insight into the complex metabolic reprogramming crucial in chondrocytes during OA progression, we investigate the dynamic interaction between metabolic pathways, such as glycolysis, lipid metabolism, and mitochondrial function. In addition, this review highlights prospective future research directions for novel approaches to diagnosis and treatment. Adopting a multifaceted strategy, our review aims to offer a comprehensive understanding of the metabolic intricacies within chondrocytes in OA, with the ultimate goal of identifying therapeutic targets capable of modulating chondrocyte metabolism for the treatment of OA.

Topics: Chondrocytes; Humans; Osteoarthritis; Animals; Cartilage, Articular; Glycolysis

PubMed: 38854686
DOI: 10.3389/fendo.2024.1393550

Authors: Yishan Chen, Yiyang Yan, Ruonan Tian...

The rapid advancement of cell therapies underscores the importance of understanding fundamental cellular attributes. Among these, cell fitness-how transplanted cells adapt to new microenvironments and maintain functional stability in vivo-is crucial. This study identifies a chemical compound, FPH2, that enhances the fitness of human chondrocytes and the repair of articular cartilage, which is typically nonregenerative. Through drug screening, FPH2 was shown to broadly improve cell performance, especially in maintaining chondrocyte phenotype and enhancing migration. Single-cell transcriptomics indicated that FPH2 induced a super-fit cell state. The mechanism primarily involves the inhibition of carnitine palmitoyl transferase I and the optimization of metabolic homeostasis. In animal models, FPH2-treated human chondrocytes substantially improved cartilage regeneration, demonstrating well-integrated tissue interfaces in rats. In addition, an acellular FPH2-loaded hydrogel proved effective in preventing the onset of osteoarthritis. This research provides a viable and safe method to enhance chondrocyte fitness, offering insights into the self-regulatory mechanisms of cell fitness.

Topics: Chondrocytes; Animals; Humans; Regeneration; Cartilage, Articular; Rats; Osteoarthritis; Hydrogels; Cell Movement

PubMed: 39259800
DOI: 10.1126/sciadv.adp4408

Authors: Huangming Zhuang, Xunshan Ren, Yuelong Zhang...

Osteoarthritis (OA) is widely recognized as the prevailing joint disease associated with aging. The ketogenic diet (KD) has been postulated to impede the advancement of various inflammatory ailments. β-Hydroxybutyrate (βOHB), a prominent constituent of ketone bodies, has recently been proposed to possess crucial signaling capabilities. In this study, we propose to explore the role and mechanism of βOHB in OA. Tissue staining and inflammatory factor assay were employed to evaluate the impacts of KD and βOHB on OA rats. The oxidative stress conditions in chondrocytes were induced using tert-butyl hydroperoxide (TBHP). The mechanisms were determined using the siRNA of hydroxycarboxylic acid receptor 2 (HCAR2), the antagonist of adenosine monophosphate-activated protein kinase (AMPK), and the inhibitor of mitophagy. The administration of KD demonstrated a reduction in pathological damage to cartilage, as well as a decrease in plasma levels of inflammatory factors. Furthermore, it resulted in an increase in the concentration of βOHB in the blood and synovial fluid. In vitro experiments showed that βOHB facilitated mitophagy and adenosine triphosphate production. Besides, βOHB mitigated chondrocyte senescence, inflammatory factors secretion, extracellular matrix degradation, and apoptosis induced by TBHP. Subsequent investigations indicated that the protective effects of βOHB were no longer observed following the knockdown of HCAR2, the antagonist of AMPK, or the inhibitor of mitophagy. Moreover, in vivo studies suggested that βOHB played a protective role by targeting the HCAR2-AMPK-PINK1 axis. In conclusion, βOHB enhanced chondrocyte mitophagy through the HCAR2/AMPK/PINK1/Parkin pathway, offering a potential therapeutic approach for the treatment of OA.

Topics: Animals; Chondrocytes; Mitophagy; Osteoarthritis; Rats; Protein Kinases; Ubiquitin-Protein Ligases; 3-Hydroxybutyric Acid; AMP-Activated Protein Kinases; Male; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Signal Transduction

PubMed: 39126207
DOI: 10.1111/acel.14294