A critical bioenergetic switch is regulated by IGF2 during murine cartilage development

Hollander, Judith M.; Li, Lingyun; Rawal, Miraj; Wang, Si Kun; Shu, Yongqian; Zhang, Ming; Nielsen, Heber C.; Rosen, Clifford J.; Zeng, Li

doi:10.1038/s42003-022-04156-4

Cited by 9 publications

(7 citation statements)

References 80 publications

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“…In support of this, these cells were enriched for pathways related to connective tissue replacement, cytokine production, and positive regulation of chemotaxis, which aligns with the secretion of angiogenic and osteoclastogenic signals by hypertrophic chondrocytes during endochondral ossification to promote vascular and osteoclast invasion into degrading cartilage [ 68 ]. Genes associated with the regulation of glycolytic and sugar metabolism pathways were also enriched; this is notable as glycolysis and oxidative phosphorylation dynamics vary at different stages of chondrocyte differentiation [ 90 ].…”

Section: Resultsmentioning

confidence: 99%

Transcriptional profiling of human cartilage endplate cells identifies novel genes and cell clusters underlying degenerated and non-degenerated phenotypes

Kuchynsky,

Stevens,

Hite

et al. 2024

Arthritis Res Ther

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Background Low back pain is a leading cause of disability worldwide and is frequently attributed to intervertebral disc (IVD) degeneration. Though the contributions of the adjacent cartilage endplates (CEP) to IVD degeneration are well documented, the phenotype and functions of the resident CEP cells are critically understudied. To better characterize CEP cell phenotype and possible mechanisms of CEP degeneration, bulk and single-cell RNA sequencing of non-degenerated and degenerated CEP cells were performed. Methods Human lumbar CEP cells from degenerated (Thompson grade ≥ 4) and non-degenerated (Thompson grade ≤ 2) discs were expanded for bulk (N=4 non-degenerated, N=4 degenerated) and single-cell (N=1 non-degenerated, N=1 degenerated) RNA sequencing. Genes identified from bulk RNA sequencing were categorized by function and their expression in non-degenerated and degenerated CEP cells were compared. A PubMed literature review was also performed to determine which genes were previously identified and studied in the CEP, IVD, and other cartilaginous tissues. For single-cell RNA sequencing, different cell clusters were resolved using unsupervised clustering and functional annotation. Differential gene expression analysis and Gene Ontology, respectively, were used to compare gene expression and functional enrichment between cell clusters, as well as between non-degenerated and degenerated CEP samples. Results Bulk RNA sequencing revealed 38 genes were significantly upregulated and 15 genes were significantly downregulated in degenerated CEP cells relative to non-degenerated cells (|fold change| ≥ 1.5). Of these, only 2 genes were previously studied in CEP cells, and 31 were previously studied in the IVD and other cartilaginous tissues. Single-cell RNA sequencing revealed 11 unique cell clusters, including multiple chondrocyte and progenitor subpopulations with distinct gene expression and functional profiles. Analysis of genes in the bulk RNA sequencing dataset showed that progenitor cell clusters from both samples were enriched in “non-degenerated” genes but not “degenerated” genes. For both bulk- and single-cell analyses, gene expression and pathway enrichment analyses highlighted several pathways that may regulate CEP degeneration, including transcriptional regulation, translational regulation, intracellular transport, and mitochondrial dysfunction. Conclusions This thorough analysis using RNA sequencing methods highlighted numerous differences between non-degenerated and degenerated CEP cells, the phenotypic heterogeneity of CEP cells, and several pathways of interest that may be relevant in CEP degeneration.

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Section: Resultsmentioning

confidence: 99%

Transcriptional profiling of human cartilage endplate cells identifies novel genes and cell clusters underlying degenerated and non-degenerated phenotypes

Kuchynsky,

Stevens,

Hite

et al. 2024

Arthritis Res Ther

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“…Besides, we also visualized the expression of genes in M8 by heatmap and bar plot, the results showed that only IGF2 was significantly up‐regulated in basal state of oral mucosa (Figure 2E,F ). IGF2 is one of the earliest discovered imprinted genes, which plays an important role in promoting cell differentiation, proliferation, and embryonic growth and development, 16 but the role of IGF2 in skin wound healing has not been fully understood.…”

Section: Resultsmentioning

confidence: 99%

Identification of IGF2 promotes skin wound healing by co‐expression analysis

Liu,

Teng,

et al. 2024

International Wound Journal

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Oral mucosa is an ideal model for studying scarless wound healing. Researchers have shown that the key factors which promote scarless wound healing already exist in basal state of oral mucosa. Thus, to identify the other potential factors in basal state of oral mucosa will benefit to skin wound healing. In this study, we identified eight gene modules enriched in wound healing stages of human skin and oral mucosa through co‐expression analysis, among which the module M8 was only module enriched in basal state of oral mucosa, indicating that the genes in module M8 may have key factors mediating scarless wound healing. Through bioinformatic analysis of genes in module M8, we found IGF2 may be the key factor mediating scarless wound healing of oral mucosa. Then, we purified IGF2 protein by prokaryotic expression, and we found that IGF2 could promote the proliferation and migration of HaCaT cells. Moreover, IGF2 promoted wound re‐epithelialization and accelerated wound healing in a full‐thickness skin wound model. Our findings identified IGF2 as a factor to promote skin wound healing which provide a potential target for wound healing therapy in clinic.

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“…An important factor in maintaining the balance between glycolysis and OXPHOS is IGF2. Hypertrophic chondrocytes from IGF2 −/− mice enhance their OXPHOS and pentose phosphate pathways [90]. Protein and lipid components, as well as nucleotide precursors, are required to ensure the anabolic boost of the hypertrophic state [90,91].…”

Section: Central Metabolic Pathways' Reprogramming and Mitochondrial ...mentioning

confidence: 99%

“…Hypertrophic chondrocytes from IGF2 −/− mice enhance their OXPHOS and pentose phosphate pathways [90]. Protein and lipid components, as well as nucleotide precursors, are required to ensure the anabolic boost of the hypertrophic state [90,91]. The first, oxidative phase of the pentose phosphate pathway produces NADPH + H + and pentoses, which can be incorporated into nucleic acids; when the second, non-oxidative phase also occurs, only NADPH + H + remains as the sole reaction product.…”

Section: Central Metabolic Pathways' Reprogramming and Mitochondrial ...mentioning

confidence: 99%

Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis

Horváth,

Sólyom,

Székely

et al. 2023

IJMS

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Osteoarthritis (OA) is a complex disease of whole joints with progressive cartilage matrix degradation and chondrocyte transformation. The inflammatory features of OA are reflected in increased synovial levels of IL-1β, IL-6 and VEGF, higher levels of TLR-4 binding plasma proteins and increased expression of IL-15, IL-18, IL-10 and Cox2, in cartilage. Chondrocytes in OA undergo hypertrophic and senescent transition; in these states, the expression of Sox-9, Acan and Col2a1 is suppressed, whereas the expression of RunX2, HIF-2α and MMP-13 is significantly increased. NF-kB, which triggers many pro-inflammatory cytokines, works with BMP, Wnt and HIF-2α to link hypertrophy and inflammation. Altered carbohydrate metabolism and the upregulation of GLUT-1 contribute to the formation of end-glycation products that trigger inflammation via the RAGE pathway. In addition, a glycolytic shift, increased rates of oxidative phosphorylation and mitochondrial dysfunction generate reactive oxygen species with deleterious effects. An important surveyor mechanism, the YAP/TAZ signaling system, controls chondrocyte differentiation, inhibits ageing by protecting the nuclear envelope and suppressing NF-kB, MMP-13 and aggrecanases. The inflammatory microenvironment and synthesis of key matrix components are also controlled by SIRT1 and mTORc. Senescent chondrocytes represent the functional end stage of hypertrophic differentiation and characteristically upregulate p16 and p21, but also a variety of inflammatory cytokines, chemokines and metalloproteinases, developing the senescence-associated secretory phenotype. Senolysis with dendrobin, miR29b-5p and other agents has been shown to be efficient under experimental conditions, and appears to be a promising tool for the treatment of OA, as it restores COL2A1 and aggrecan synthesis, suppressing NF-kB and destructive metalloproteinases.

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A critical bioenergetic switch is regulated by IGF2 during murine cartilage development

Cited by 9 publications

References 80 publications

Transcriptional profiling of human cartilage endplate cells identifies novel genes and cell clusters underlying degenerated and non-degenerated phenotypes

Transcriptional profiling of human cartilage endplate cells identifies novel genes and cell clusters underlying degenerated and non-degenerated phenotypes

Identification of IGF2 promotes skin wound healing by co‐expression analysis

Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis

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