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Long noncoding RNA H19 alleviates inflammation in osteoarthritis through interactions between TP53, IL-38, and IL-36
Yeli Zhou1, Jing Li1, Feng Xu2
1Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Aims:
Osteoarthritis (OA) is a common degenerative joint disease characterized by chronic inflammatory articular cartilage degradation. Long noncoding RNAs (lncRNAs) have been previously indicated to play an important role in inflammation-related diseases. Herein, the current study set out to explore the involvement of lncRNA H19 in OA.
Methods:
Firstly, OA mouse models and interleukin (IL)-1β-induced mouse chondrocytes were established. Expression patterns of IL-38 were determined in the synovial fluid and cartilage tissues from OA patients. Furthermore, the targeting relationship between lncRNA H19, tumour protein p53 (TP53), and IL-38 was determined by means of dual-luciferase reporter gene, chromatin immunoprecipitation, and RNA immunoprecipitation assays. Subsequent to gain- and loss-of-function assays, the levels of cartilage damage and proinflammatory factors were further detected using safranin O-fast green staining and enzyme-linked immunosorbent assay (ELISA) in vivo, respectively, while chondrocyte apoptosis was measured using Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) in vitro.
Results:
IL-38 was highly expressed in lentivirus vector-mediated OA mice. Meanwhile, injection of exogenous IL-38 to OA mice alleviated the cartilage damage, and reduced the levels of proinflammatory factors and chondrocyte apoptosis. TP53 was responsible for lncRNA H19-mediated upregulation of IL-38. Furthermore, it was found that the anti-inflammatory effects of IL-38 were achieved by its binding with the IL-36 receptor (IL-36R). Overexpression of H19 reduced the expression of inflammatory factors and chondrocyte apoptosis, which was abrogated by knockdown of IL-38 or TP53.
Conclusion:
Collectively, our findings evidenced that upregulation of lncRNA H19 attenuates inflammation and ameliorates cartilage damage and chondrocyte apoptosis in OA by upregulating TP53, IL-38, and by activating IL-36R.Cite this article: Bone Joint Res 2022;11(8):594-607.
Insights
Long noncoding RNA H19 (lncRNA H19) attenuates osteoarthritis (OA) inflammation and cartilage damage. It achieves this by upregulating tumor protein p53 (TP53) and interleukin-38 (IL-38), which activates the IL-36 receptor (IL-36R).
Area of Science:
- Molecular Biology
- Immunology
- Rheumatology
Background:
- Osteoarthritis (OA) is a degenerative joint disease with chronic inflammation and cartilage degradation.
- Long noncoding RNAs (lncRNAs) are implicated in inflammatory diseases, prompting investigation into their role in OA.
Purpose of the Study:
- To explore the involvement of lncRNA H19 in the pathogenesis of osteoarthritis.
- To elucidate the molecular mechanisms by which lncRNA H19 influences OA progression.
Main Methods:
- Established OA mouse models and IL-1β-induced chondrocyte models.
- Assessed expression of IL-38 in OA patient samples.
- Utilized dual-luciferase reporter, ChIP, and RIP assays to determine interactions between lncRNA H19, TP53, and IL-38.
- Conducted gain- and loss-of-function studies, alongside in vivo and in vitro analyses of cartilage damage, inflammation, and apoptosis.
Main Results:
- Interleukin-38 (IL-38) expression was elevated in OA models and patients; exogenous IL-38 alleviated OA symptoms.
- Tumor protein p53 (TP53) mediated lncRNA H19's upregulation of IL-38.
- IL-38 exerted anti-inflammatory effects by binding to the IL-36 receptor (IL-36R).
- Overexpression of H19 reduced inflammation and chondrocyte apoptosis, effects dependent on IL-38 and TP53.
Conclusions:
- Upregulation of lncRNA H19 attenuates OA inflammation, cartilage damage, and chondrocyte apoptosis.
- The mechanism involves the upregulation of TP53 and IL-38, leading to IL-36R activation.
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