Expression and Role of IL-1β Signaling in Chondrocytes Associated with Retinoid Signaling during Fracture Healing

Abstract

The process of fracture healing consists of an inflammatory reaction and cartilage and bone tissue reconstruction. The inflammatory cytokine interleukin-1β (IL-1β) signal is an important major factor in fracture healing, whereas its relevance to retinoid receptor (an RAR inverse agonist, which promotes endochondral bone formation) remains unclear. Herein, we investigated the expressions of IL-1β and retinoic acid receptor gamma (RARγ) in a rat fracture model and the effects of IL-1β in the presence of one of several RAR inverse agonists on chondrocytes. An immunohistochemical analysis revealed that IL-1β and RARγ were expressed in chondrocytes at the fracture site in the rat ribs on day 7 post-fracture. In chondrogenic ATDC5 cells, IL-1β decreases the levels of aggrecan and type II collagen but significantly increased the metalloproteinase-13 (Mmp13) mRNA by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. An RAR inverse agonist (AGN194310) inhibited IL-1β-stimulated Mmp13 and Ccn2 mRNA in a dose-dependent manner. Phosphorylated extracellular signal regulated-kinases (pERK1/2) and p-p38 mitogen-activated protein kinase (MAPK) were increased time-dependently by IL-1β treatment, and the IL-1β-induced p-p38 MAPK was inhibited by AGN194310. Experimental p38 inhibition led to a drop in the IL-1β-stimulated expressions of Mmp13 and Ccn2 mRNA. MMP13, CCN2, and p-p38 MAPK were expressed in hypertrophic chondrocytes near the invaded vascular endothelial cells. As a whole, these results point to role of the IL-1β via p38 MAPK as important signaling in the regulation of the endochondral bone formation in fracture healing, and to the actions of RAR inverse agonists as potentially relevant modulators of this process.

Retinol-Loaded Poly(vinyl alcohol)-Based Hydrogels as Suitable Biomaterials with Antimicrobial Properties for the Proliferation of Mesenchymal Stem Cells

“…In addition, several studies have already proven the beneficial effects of retinol on the immune and therapeutic systems [ 28 ]. In addition, the cell proliferative effect of retinol was substantially proven in several studies performed with stem cells [ 29 ], fibroblasts [ 30 ], chondrocytes [ 31 ], keratinocytes, and bone cells [ 32 , 33 ]. Recently, the use of retinol in biomedical applications is an increasing trend, and several novel approaches have been initiated to better use and overcome the major drawbacks of retinol in the practical field.…”

Cartilage Destruction by Hemophilic Arthropathy Can Be Prevented by Inhibition of the Ferroptosis Pathway in Human Chondrocytes

“…The role of IL-1ß merits further discussion; it appears to have variable effects depending on the cell type, cytokine concentration, and duration of exposure. While some research indicates IL-1ß may encourage chondrocyte proliferation [42], others suggest it can signal programmed cell death [43]. The complexities of IL-1ß's impact on chondrocytes suggest it is modulated by various factors, including the local environment, cytokine levels, tissue health, and the presence of other inflammatory or healing agents [42,43].…”

Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of Ccn2

“…Indeed, it has been shown in vitro that CCN2 induces chondrocyte proliferation and differentiation, with increased synthesis of cartilage matrix proteins, including proteoglycans, ACAN and collagen types II and X ( Shimo et al, 2000 ; Fujisawa et al, 2008 ). Subsequently, it was found that CCN2 plays a role in chondrogenesis during fractured bone healing; CCN2 expression in this process responds to MAPK and retinoid receptor gamma signalling pathways ( Shimo et al, 2019 , 2005 , 2020 ; Nakata et al, 2002 ; Yosimichi et al, 2006 ). CCN2 expression is highly regulated by TGFβ ( Song et al, 2007 ), with its promoter transcriptional activity maintained by a TGFβ response element ( Eguchi et al, 2001 ).…”