Disruption of phosphoinositide-specific phospholipases Cγ1 contributes to extracellular matrix synthesis of human osteoarthritis chondrocytes.

Guoqing Zeng,Bing Zhang,Xinpeng Zheng,Honghai Zhao,Zejun Liu,Chun Xia,Xu Cui

doi:10.3390/ijms150813236

Abstract

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation including extracellular matrix (ECM) degradation and cell loss. It is known that phosphoinositide-specific phospholipase γ1 (PLCγ1) can trigger several signaling pathways to regulate cell metabolism. However, whether this kinase is expressive and active in human OA chondrocytes and its role in the pathological progression of OA have not been investigated. The current study was designed to investigate the PLCγ1 expression in human OA cartilage, and whether PLCγ1 was involved in the ECM synthesis had been further explored using cultured human OA chondrocytes. Our results indicated that PLCγ1 was highly expressed in human OA chondrocytes. In our further study using the cultured human OA chondrocytes, the results demonstrated that the disruption of PLCγ1 by its inhibitor, U73122, and siRNA contributed to the ECM synthesis of human OA chondrocytes through regulating the expression of ECM-related signaling molecules, including MMP-13, Col II, TIMP1, Sox-9, and AGG. Furthermore, PLCγ1/IP3/Ca(2+)/CaMK II signaling axis regulated the ECM synthesis of human chondrocytes through triggering mTOR/P70S6K/S6 pathway. In summary, our results suggested that PLC-γ1 activities played an important role in the ECM synthesis of human OA chondrocytes, and may serve as a therapeutic target for treating OA.

Highlights

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation including extracellular matrix (ECM) degradation and cell loss
PLC-γ1 Is Highly Expressed in Human OA Chondrocytes
The results depicted that the expression levels of PLCγ1 and p-PLCγ1-Tyr783, which is essential for PLCγ1 activation [1], were higher in human OA chondrocytes than normal chondrocytes (Figure 1A, * p < 0.05)

Summary

Introduction

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation including extracellular matrix (ECM) degradation and cell loss. The main components of ECM in cartilage are proteoglycans and collagenous network, and the loss of aggrecan (a negatively charged proteoglycan, AGG) and type II collagen (Col II) in ECM is the primary event leading to cartilage degradation [1]. It has been shown that collagens and aggrecan can be directly cleaved by matrix metalloproteinases (MMPs) and aggrecanases (ADAMTSs), both of which are regulated by some key signaling molecules. MMP-2, MMP-9, and MMP-13 are activated by APC in human osteoarthritic cartilage chondrocytes [2]. Adaptor Proteins and Ras synergistically regulate IL-1-Induced ADAMTS-4 expression in human Chondrocytes [3]. The signaling regulatory mechanism is not fully elucidated

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Results

Conclusion