HMGB2 promotes chondrocyte proliferation under negative pressure through the phosphorylation of AKT

Liu, Qian; He, Feng; Zhou, Peng; Xie, Mianjiao; Wang, Helin; Yang, Hongxu; Huo, Wanqiu; Zhang, Mian; Yu, Shuxun; Wang, Meiqing

doi:10.1016/j.bbamcr.2021.119115

Cited by 7 publications

(5 citation statements)

References 40 publications

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“…In the BAE mouse model, HMGB2 upregulation was observed in thickened condylar cartilage. The authors confirmed in vitro that under negative pressure, HMGB2 was upregulated in superficial condylar chondrocytes and stimulated proliferation via activation of the AKT signaling pathway ( Liu et al, 2021b ).…”

Section: Moderate Mechanical Stimulationmentioning

confidence: 76%

Critical signaling molecules in the temporomandibular joint osteoarthritis under different magnitudes of mechanical stimulation

Liu,

Jia,

et al. 2024

Front. Pharmacol.

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The mechanical stress environment in the temporomandibular joint (TMJ) is constantly changing due to daily mandibular movements. Therefore, TMJ tissues, such as condylar cartilage, the synovial membrane and discs, are influenced by different magnitudes of mechanical stimulation. Moderate mechanical stimulation is beneficial for maintaining homeostasis, whereas abnormal mechanical stimulation leads to degeneration and ultimately contributes to the development of temporomandibular joint osteoarthritis (TMJOA), which involves changes in critical signaling molecules. Under abnormal mechanical stimulation, compensatory molecules may prevent degenerative changes while decompensatory molecules aggravate. In this review, we summarize the critical signaling molecules that are stimulated by moderate or abnormal mechanical loading in TMJ tissues, mainly in condylar cartilage. Furthermore, we classify abnormal mechanical stimulation-induced molecules into compensatory or decompensatory molecules. Our aim is to understand the pathophysiological mechanism of TMJ dysfunction more deeply in the ever-changing mechanical environment, and then provide new ideas for discovering effective diagnostic and therapeutic targets in TMJOA.

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Section: Moderate Mechanical Stimulationmentioning

confidence: 76%

Critical signaling molecules in the temporomandibular joint osteoarthritis under different magnitudes of mechanical stimulation

Liu,

Jia,

et al. 2024

Front. Pharmacol.

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“…Notably, several studies have found that HMGB2 plays a role in chondrocytes. For instance, previous studies have indicated that chondrocyte senescence is associated with a loss of HMGB2 expression, and HMGB2 promotes chondrocyte proliferation ( 53 , 54 ). Studies on the molecular mechanism of HMGB2 have shown that HMGB2-mediated genomic reorganization initiates a senescence program and holds the key to the senescence-associated secretory phenotype ( 36 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell protein activity analysis reveals a novel subpopulation of chondrocytes and the corresponding key master regulator proteins associated with anti-senescence and OA progression

et al. 2023

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BackgroundOsteoarthritis (OA) is a prevalent senescence-related disease with substantial joint pain, loss of joint function, and cartilage degeneration. Because of the paucity of single-cell studies of OA and the gene dropout problem of single-cell RNA sequencing, it is difficult to acquire an in-depth understanding of the molecular characteristics of various chondrocyte clusters.MethodsHere, we aimed to provide new insights into chondrocyte senescence and a rationale for the development of effective intervention strategies for OA by using published single-cell RNA-sequencing data sets and the metaVIPER algorithm (Virtual Inference of Protein activity by Enriched Regulon). This algorithm was employed to present a proteome catalog of 62,449 chondrocytes from the cartilage of healthy individuals and OA patients at single-cell resolution. Furthermore, histopathologic analysis was carried out in cartilage samples from clinical patients and experimental mouse models of OA to validate above results.ResultsWe identified 16 protein-activity-based chondrocyte clusters as well as the underlying master regulators in each cluster. By assessing the enrichment score of each cluster in bulk RNA-sequencing data, followed by gene-set variation analysis, we preliminarily identified a novel subpopulation of chondrocytes (cluster 3). This clinically relevant cluster was predicted to be the main chondrocyte cluster responsible for maintaining cellular homeostasis and anti-senescence. Specifically, we uncovered a set of the key leading-edge proteins of cluster 3 by validating the robustness of the above results using another human chondrocyte single-cell RNA-sequencing data set, consisting of 24,675 chondrocytes. Furthermore, cartilage samples from clinical patients and experimental mouse models of OA were used to evaluate the expression patterns of these leading-edge proteins, and the results indicated that NDRG2, TSPYL2, JMJD6 and HMGB2 are closely associated with OA pathogenesis and might play critical roles in modulating cellular homeostasis and anti-senescence in chondrocytes.ConclusionOur study revealed a novel subpopulation of chondrocytes that are critical for anti-progression of OA and the corresponding master regulator proteins, which might serve as therapeutic targets in OA.

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“…In addition, in the present study the PI3K/AKT pathway mediated p67-induced SOX9, COL2A1, and ACAN production. The PI3K/AKT pathway has been implicated in chondrocyte proliferation and survival, 52 , 53 chondrogenic differentiation, hypertrophic maturation, and ECM deposition. 54 , 55 As shown in Figure 7 , overexpression of p67 phox in chondrocytes activated AKT phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Suramin enhances chondrogenic properties by regulating the p67^phox/PI3K/AKT/SOX9 signalling pathway

Liu

Shen

et al. 2022

Bone & Joint Research

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Aims Autologous chondrocyte implantation (ACI) is a promising treatment for articular cartilage degeneration and injury; however, it requires a large number of human hyaline chondrocytes, which often undergo dedifferentiation during in vitro expansion. This study aimed to investigate the effect of suramin on chondrocyte differentiation and its underlying mechanism. Methods Porcine chondrocytes were treated with vehicle or various doses of suramin. The expression of collagen, type II, alpha 1 (COL2A1), aggrecan (ACAN); COL1A1; COL10A1; SRY-box transcription factor 9 (SOX9); nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX); interleukin (IL)-1β; tumour necrosis factor alpha (TNFα); IL-8; and matrix metallopeptidase 13 (MMP-13) in chondrocytes at both messenger RNA (mRNA) and protein levels was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot. In addition, the supplementation of suramin to redifferentiation medium for the culture of expanded chondrocytes in 3D pellets was evaluated. Glycosaminoglycan (GAG) and collagen production were evaluated by biochemical analyses and immunofluorescence, as well as by immunohistochemistry. The expression of reactive oxygen species (ROS) and NOX activity were assessed by luciferase reporter gene assay, immunofluorescence analysis, and flow cytometry. Mutagenesis analysis, Alcian blue staining, reverse transcriptase polymerase chain reaction (RT-PCR), and western blot assay were used to determine whether p67phox was involved in suramin-enhanced chondrocyte phenotype maintenance. Results Suramin enhanced the COL2A1 and ACAN expression and lowered COL1A1 synthesis. Also, in 3D pellet culture GAG and COL2A1 production was significantly higher in pellets consisting of chondrocytes expanded with suramin compared to controls. Surprisingly, suramin also increased ROS generation, which is largely caused by enhanced NOX (p67phox) activity and membrane translocation. Overexpression of p67phox but not p67phoxAD (deleting amino acid (a.a) 199 to 212) mutant, which does not support ROS production in chondrocytes, significantly enhanced chondrocyte phenotype maintenance, SOX9 expression, and AKT (S473) phosphorylation. Knockdown of p67phox with its specific short hairpin (sh) RNA (shRNA) abolished the suramin-induced effects. Moreover, when these cells were treated with the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) inhibitor LY294002 or shRNA of AKT1, p67phox-induced COL2A1 and ACAN expression was significantly inhibited. Conclusion Suramin could redifferentiate dedifferentiated chondrocytes dependent on p67phox activation, which is mediated by the PI3K/AKT/SOX9 signalling pathway. Cite this article: Bone Joint Res 2022;11(10):693–708.

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HMGB2 promotes chondrocyte proliferation under negative pressure through the phosphorylation of AKT

Cited by 7 publications

References 40 publications

Critical signaling molecules in the temporomandibular joint osteoarthritis under different magnitudes of mechanical stimulation

Critical signaling molecules in the temporomandibular joint osteoarthritis under different magnitudes of mechanical stimulation

Single-cell protein activity analysis reveals a novel subpopulation of chondrocytes and the corresponding key master regulator proteins associated with anti-senescence and OA progression

Suramin enhances chondrogenic properties by regulating the p67^phox/PI3K/AKT/SOX9 signalling pathway

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HMGB2 promotes chondrocyte proliferation under negative pressure through the phosphorylation of AKT

Cited by 7 publications

References 40 publications

Critical signaling molecules in the temporomandibular joint osteoarthritis under different magnitudes of mechanical stimulation

Critical signaling molecules in the temporomandibular joint osteoarthritis under different magnitudes of mechanical stimulation

Single-cell protein activity analysis reveals a novel subpopulation of chondrocytes and the corresponding key master regulator proteins associated with anti-senescence and OA progression

Suramin enhances chondrogenic properties by regulating the p67phox/PI3K/AKT/SOX9 signalling pathway

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Suramin enhances chondrogenic properties by regulating the p67^phox/PI3K/AKT/SOX9 signalling pathway