Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide. However, effective strategies for cartilage repair are lacking, and patients with advanced OA usually need joint replacement. Better comprehending OA pathogenesis may lead to transformative therapeutics. Recently studies have reported that exosomes act as a new means of cell-to-cell communication by delivering multiple bioactive molecules to create a particular microenvironment that tunes cartilage behavior. Specifically, exosome cargos, such as noncoding RNAs (ncRNAs) and proteins, play a crucial role in OA progression by regulating the proliferation, apoptosis, autophagy, and inflammatory response of joint cells, rendering them promising candidates for OA monitoring and treatment. This review systematically summarizes the current insight regarding the biogenesis and function of exosomes and their potential as therapeutic tools targeting cell-to-cell communication in OA, suggesting new realms to improve OA management.
Apoptosis ; Cartilage/pathology* ; Cartilage, Articular/metabolism* ; Cell Communication ; Chondrocytes/metabolism* ; Exosomes/pathology* ; Humans ; Osteoarthritis/therapy*

Experimental findings have suggested that the metabolic activities of articular cartilage can be influenced by mechanical stimuli. Our recent mathematical analysis predicted that cyclic compressive loading may create periods of intermittent negative hydrostatic pressure within the cartilage extracellular matrix. Therefore, we hypothesize that intermittent negative hydrostatic pressure, created in the cartilage extracellular matrix during dynamic compression, has a stimulative effect on the biosynthesis of chondrocytes. In order to test this hypothesis, the present study developed a custom designed negative pressure generator to subject a monolayer culture of chondrocytes to an intermittent negative pressure. It was found that the intermittent negative pressure produced a 40% increase in proteoglycan and a l7% increase in non-collagenous protein synthesis during the pressurization period(p (0.05). The collagenous protein synthesis was not affected by the intermittent negative pressure regimen used in this study. After the intermittent negative pressurization, the metabolic activities of the chondrocytes returned to normal(control level). The intermittent negative pressure also produced an increase in the mRNA signals for aggrecan. Therefore, we conclude that intermittent negative pressure may be one of the major mechanical stimulators of chondrocytes in articular cartilage during dynamic compression.
Aggrecans ; Cartilage ; Cartilage, Articular ; Chondrocytes* ; Collagen ; Extracellular Matrix ; Hydrostatic Pressure* ; Metabolism* ; Proteoglycans ; RNA, Messenger

OBJECTIVE: To summarize the role of chondrocyte mitochondrial homeostasis imbalance in the pathogenesis of osteoarthritis (OA) and analyze its application prospects. METHODS: The recent literature at home and abroad was reviewed to summarize the mechanism of mitochondrial homeostasis imbalance, the relationship between mitochondrial homeostasis imbalance and the pathogenesis of OA, and the application prospect in the treatment of OA. RESULTS: Recent studies have shown that mitochondrial homeostasis imbalance, which is caused by abnormal mitochondrial biogenesis, the imbalance of mitochondrial redox, the imbalance of mitochondrial dynamics, and damaged mitochondrial autophagy of chondrocytes, plays an important role in the pathogenesis of OA. Abnormal mitochondrial biogenesis can accelerate the catabolic reaction of OA chondrocytes and aggravate cartilage damage. The imbalance of mitochondrial redox can lead to the accumulation of reactive oxygen species (ROS), inhibit the synthesis of extracellular matrix, induce ferroptosis and eventually leads to cartilage degradation. The imbalance of mitochondrial dynamics can lead to mitochondrial DNA mutation, decreased adenosine triphosphate production, ROS accumulation, and accelerated apoptosis of chondrocytes. When mitochondrial autophagy is damaged, dysfunctional mitochondria cannot be cleared in time, leading to ROS accumulation, which leads to chondrocyte apoptosis. It has been found that substances such as puerarin, safflower yellow, and astaxanthin can inhibit the development of OA by regulating mitochondrial homeostasis, which proves the potential to be used in the treatment of OA. CONCLUSION The mitochondrial homeostasis imbalance in chondrocytes is one of the most important pathogeneses of OA, and further exploration of the mechanisms of mitochondrial homeostasis imbalance is of great significance for the prevention and treatment of OA.
Humans ; Reactive Oxygen Species/metabolism* ; Chondrocytes/metabolism* ; Osteoarthritis/metabolism* ; Homeostasis ; Mitochondria/metabolism* ; Cartilage, Articular/metabolism*

OBJECTIVE: To investigate whether Salvianolic acid A (SAA) can restore cartilage endplate cell degeneration of intervertebral discs and to identify the mechanism via regulation of micro-RNA. METHODS: Cartilage endplate cells were isolated from lumbar intervertebral disc surgical samples and were treated with serum containing a series of concentrations of SAA (2, 5, and 10 ?M) for 24, 48, and 72 h to identify a proper dose and treatment time of SAA. The effect SAA on interlenkin-1β (IL-1β)-induced extracellular matrix degradation of cartilage endplate cells were analyzed by Alcian blue staining and assessment of the expression levels of ADAMTS-5, MMP3 and Col2a1. Further, the potential target miRNAs were preliminarily screened by micro-RNA sequencing combining qRT-PCR and Western blot, and then, the miRNAs mimics and inhibitors were used to verify the regulatory effect of SAA on potential target miRNAs. RESULTS: The 10 μM SAA treatment for 48 h significantly enhanced the viability of cartilage endplate cells, and increased Col2a1 expression and glycosaminoglycan accumulation that were repressed by IL-1β, and reduced the effect of IL-1β on ADAMTS-5, and MMP3. Screening analysis based on micro-RNA sequencing and Venny analysis identified the downstream micro-RNAs, including miR-940 and miR-576-5p. Then, the miR-940-mimic or miR-576-5p-mimic were transfected into CEPCs. Compared with the SAA group, the expression of ADAMTS-5 and MMP3 increased significantly and the expression of COL2A1 obviously decreased after overexpression of miR-940 or miR-576-5p in CEPCs. CONCLUSION Salvianolic acid A attenuated the IL-1β-induced extracellular matrix degradation of cartilage endplate cells by targeting regulate the miR-940 and the miR-576-5p.
Humans ; Apoptosis ; Cartilage/metabolism* ; Chondrocytes/metabolism* ; Interleukin-1beta/metabolism* ; Matrix Metalloproteinase 3/metabolism* ; MicroRNAs/metabolism*

OBJECTIVE: To assess the efficacy of GelMA hydrogel loaded with bone marrow stem cell-derived exosomes for repairing injured rat knee articular cartilage. METHODS: The supernatant of cultured bone marrow stem cells was subjected to ultracentrifugation separate and extract the exosomes, which were characterized by transmission electron microscopy, particle size analysis and Western blotting of the surface markers. The changes in rheology and electron microscopic features of GelMA hydrogel were examined after loading the exosomes. We assessed exosome release from the hydrogel was detected by BCA protein detection method, and labeled the exosomes with PKH26 red fluorescent dye to observe their phagocytosis by RAW264.7 cells. The effects of the exosomes alone, unloaded hydrogel, and exosome-loaded hydrogel on the polarization of RAW264.7 cells were detected by q-PCR and immunofluorescence assay. We further tested the effect of the exosome-loaded hydrogel on cartilage repair in a Transwell co-culture cell model of RAW264.7 cells and chondrocytes in a rat model of knee cartilage injury using q-PCR and immunofluorescence assay and HE and Masson staining. RESULTS: GelMA hydrogel loaded with exosomes significantly promoted M2-type polarization of RAW264.7 cells (P < 0.05). In the Transwell co-culture model, the exosome-loaded GelMA hydrogel significantly promoted the repair of injured chondrocytes by regulating RAW264.7 cell transformation from M1 to M2 (P < 0.05). HE and Masson staining showed that the exosome-loaded hydrogel obviously promoted cartilage repair in the rat models damage. CONCLUSION GelMA hydrogel loaded with bone marrow stem cell-derived exosomes can significantly promote the repair of cartilage damage in rats by improving the immune microenvironment.
Animals ; Bone Marrow Cells ; Cartilage ; Chondrocytes ; Exosomes ; Hydrogels/metabolism* ; Rats

With the effects of the mechanics and biological factors, the imbalance between the degradation and synthesis of chondrocyte, extracelluar matrix and subchondral bone leads to the osteoarthritis. The imbalance between MMPs and TIMPs caused by biomechanical abnormality is the key factor of osteoarthritis. This review will focus on the stress and their roles in the metabolism of the cartilage matrix.
Cartilage ; metabolism ; Humans ; Matrix Metalloproteinases ; metabolism ; Osteoarthritis ; metabolism ; Stress, Mechanical ; Tissue Inhibitor of Metalloproteinases ; metabolism

In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.
Mice ; Animals ; Hedgehog Proteins/genetics* ; Receptors, G-Protein-Coupled/metabolism* ; Cilia/metabolism* ; Cartilage/metabolism* ; Regeneration

To investigate the estrogen receptor (ER) expression in cartilage cell in the development of osteoarthritis induced by bilateral ovariectomy in guinea pig and to find their relationship. 30 two-month-old female guinea pigs were randomly divided into two groups (n = 15 each): sham operation (control) group and ovariectomized group (OVX); Scanning electorne microscope (SEM) and transmission electron microscope (TEM) were obtained to analysis the cartilage degeneration of the hind limb knee joint after 6 and 12 weeks of ovariectomy. Dextran-Coated-Charcoal (DCC) was taken to quantitively detect the expression of ER. The serum levels of estrogen and gestone were detected by immune contest assay. The results showed that ER do exist in the cartilages of the guinea pigs, with higher expression in the control group than in OVX group at the same time point (P < 0.05). It was increased also at 12 th week after operation than that of preoperation. The blood serum levels of estrogen and gestone showed a similar tendency to the expression of ER. Joint cartilage degeneration detected by SEM and TEM could be found at 6 th week, but severe degenerative lesions at 12 th week in the OVX group compared with the control group (P < 0.01). The data suggested that bilateral ovariectomy in guinea pig lead to severe osteoarthritis which mighgt be related to the lower serum level of estrogen and the downregulation of the expression of ER in the cartilage also.
Cartilage, Articular/cytology ; Cartilage, Articular/*metabolism ; Chondrocytes/metabolism ; Estrogens/*blood ; Osteoarthritis/*etiology ; Osteoarthritis/metabolism ; Ovariectomy ; Random Allocation ; Receptors, Estrogen/*biosynthesis ; Receptors, Estrogen/genetics

The changes of hyaline articular cartilage from rabbits after air exposure were evaluated. The knee joints were exposed to air for periods of thirty minutes to two hours. The animals were killed periodically, at three days, one week and three weeks postoperatively. After sacrifice, the cartilage was removed and prepared for study by light microscopy and electron microscopy. Exposure to room air for thirty minutes produced chondrocyte necrosis in the upper third of the cartilage, and exposure for 60 minutes or longer produced chondrocyte necrosis of the entire thickness of articular cartilage at three days after arthrotomy. But, three weeks after arthrotomy, we could not find any chondrocyte necrosis in any rabbits at varying periods of air exposure. There was no significant change in proteoglycan content between the aired and control cartilage. Clinical Relevance: Exposing cartilage to air can cause transient and reversible cartilage damage. If these changes are not reversible, the orthopedic surgeon should consider avoiding the prolonged exposure of articular cartilage to air, since complete matrix disintegration is known to occur months after chondrocyte necrosis.
*Air ; Animal ; Cartilage, Articular/metabolism/*pathology/ultrastructure ; Hyalin/*metabolism ; Microscopy, Electron ; Necrosis ; Rabbits ; Time Factors

Cartilage, Articular ; metabolism ; Humans ; Osteoarthritis, Knee ; blood ; Platelet-Rich Plasma ; metabolism