Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Abstract

Osteoarthritis (OA) is the most common chronic degenerative joint disease, and it remains the main cause of chronic disability in elderly individuals. Sema4D (semaphorin 4D) is involved in the immune system and related to bone injury, osteoporosis, osteoblast differentiation, and rheumatoid arthritis. However, the role of Sema4D in OA remains unclear. Hence, the LPS-stimulated chondrocyte cell injury model was constructed in this study to investigate the role of Sema4D in OA development. The results showed that Sema4D was increased in LPS-treated ATDC5 cells, and the knockdown of Sema4D suppressed the decline of cell viability, the increase of cell apoptosis, and the increase of IL-6, IL-1β, and TNF-α secretion in ATDC5 cells induced by LPS. Meanwhile, Sema4D overexpression aggravated the cell injury triggered by LPS, and inhibiting Plexin B1 partly abolished the effect of Sema4D overexpression on LPS-induced chondrocyte injury. Furthermore, silencing of Sema4D blocked the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. Enhanced Sema4D promoted the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. What is more, inhibiting the MAPK signaling pathway abolished the promoting effect of Sema4D overexpression on LPS-induced chondrocyte injury. Therefore, our study suggested that the knockdown of Sema4D protects ATDC5 cells against LPS-induced injury through inactivation of the MAPK signaling pathway via interacting with Plexin B1.

Inhibition of SDF-1/CXCR4 Axis to Alleviate Abnormal Bone Formation and Angiogenesis Could Improve the Subchondral Bone Microenvironment in Osteoarthritis

“…At present, abnormal angiogenesis in the subchondral bone leads to invasion of vasculature into the osteochondral junction is a hallmark of human osteoarthritis [46]. Type H 7 BioMed Research International vessels, characterized by high expression of endothelial markers CD31 and Emcn (CD31 hi Emcn hi ), produce a unique microenvironment to maintain perivascular bone progenitor cells and to link angiogenesis to bone progenitor cells [46].…”

“…It is commonly agreed that the activated ERK pathway of MSCs could obviously promote osteogenic differentiation [ 45 ]. In addition, it has been reported that inhibition of the MAPK signaling pathway can effectively protect chondrocytes from damage caused by factors such as Sema4D, which indicate that the MAPK signaling pathway may play an important role in OA [ 46 ]. In the present study, we found out that SDF-1 could obviously activate the ERK signaling which may indicate that SDF-1 may have promoted BMSC migration and osteogenic differentiation through the ERK signal pathway.…”

“…At present, abnormal angiogenesis in the subchondral bone leads to invasion of vasculature into the osteochondral junction is a hallmark of human osteoarthritis [ 46 ]. Type H vessels, characterized by high expression of endothelial markers CD31 and Emcn (CD31 hi Emcn hi ), produce a unique microenvironment to maintain perivascular bone progenitor cells and to link angiogenesis to bone progenitor cells [ 46 ]. Several previous studies suggested that neovessel formation in the subchondral bone is characterized by the development of osteogenesis-coupling type H vessels (CD31 hi Emcn hi ) [ 14 , 47 , 48 ].…”

DUSP4 alleviates LPS‑induced chondrocyte injury in knee osteoarthritis via the MAPK signaling pathway

“…The results of a previous study indicated that DUSP4 silencing in diabetes enhanced the activity of the p38/JNK signaling pathway ( 27 ). Additionally, simultaneously activating the MAPK signaling pathway aggravated LPS-induced chondrocyte injury ( 28 ). Ham et al ( 25 ) revealed an association between LPS, DUSPs and ERK1/2 in microglia cells, and highlighted that LPS induced ERK1/2 phosphorylation, thereby regulating the expression of DUSP4 and 6.…”

Neutrophil-Derived Semaphorin 4D Induces Inflammatory Cytokine Production of Endothelial Cells via Different Plexin Receptors in Kawasaki Disease

“…By binding to different receptors, sSema4D exhibits different effects on the inflammatory phenotype in different types of cells. For instance, the Sema4D-plexin B1 axis promoted the inflammation of chondrocytes [ 15 ], whereas the Sema4D-plexin B2 axis contributed to the keratinocyte's inflammation [ 16 ]. Interestingly, studies have shown that both plexin B1 and plexin B2 are expressed on the surface of human ECs [ 17 , 18 ].…”