Elevated expression of MMP8 and MMP9 contributes to diabetic osteoarthritis progression in a rat model

Simin Luo,Wuji Li,Qiping Shi,Wenrui Wu

doi:10.1186/s13018-021-02208-9

Abstract

BackgroundKnowledge regarding the pathogenesis of osteoarthritis (OA) is very limited. Previous studies have shown that matrix metalloproteinase (MMP) 8 and MMP9 were upregulated in patients with diabetic OA. However, their regulatory functions and mechanisms in diabetic OA are not fully understood.MethodsDiabetic OA rats were constructed using a high-fat diet combined with streptozotocin (STZ) induction. Safranin O-Fast green staining was used to detect the pathological changes in rat knee cartilage. MMP8 and MMP9 overexpression vectors or siRNAs were injected into diabetic OA rats to overexpress or knockdown the expression of MMP8 and MMP9, which was verified by real-time quantitative PCR (RT-qPCR). The expression of MMP8 and MMP9, chondrocyte differentiation markers collagen type II alpha 1 (COL2A1) and collagen type I alpha 1(COL1A1), and antiapoptotic protein BCL2 were detected using immunohistochemistry (IHC), and the number of apoptotic cells was detected by the transferase-mediated d-UTP nick-end-labeling (TUNEL) assay.ResultsHigh-fat diet combined with STZ-induced rats exhibited joint cartilage damage, morphological changes, and increased expression of MMP8 and MMP9. Overexpression of MMP8 and MMP9 in the joint cavity further aggravated the pathological morphological changes, decreased the expression of COL2A1 and COL1A1, increased the expression of BCL2, and promoted cell apoptosis in diabetic OA rats. The use of siRNA to inhibit MMP8 and MMP9 levels in the cartilage joints significantly reversed the decrease in COL2A1 and COL1A1 expression and partially reversed BCL2 expression and chondrocyte apoptosis.ConclusionMMP8 and MMP9 promoted rat diabetic OA model. The underlying mechanism may be related to inhibiting cartilage differentiation and promoting chondrocyte apoptosis.

Highlights

Osteoarthritis (OA) is the most common chronic degenerative disease in the elderly population [1]
We found that the overexpression of MMP8 and MMP9 inhibited the expression of antiapoptotic protein BCL2 and increased the number of apoptotic chondrocytes in diabetic OA rats, whereas inhibition of MMP8 and MMP9 partially reversed this proapoptotic effect
We found that the expression of antiapoptotic protein BCL2 was suppressed, and the apoptosis of diabetic OA rat chondrocytes was promoted by MMP8 and MMP9 overexpression and alleviated by siRNA treatments

Summary

Introduction

Osteoarthritis (OA) is the most common chronic degenerative disease in the elderly population [1]. OA frequently coexist [5], and type 2 diabetes mellitus is closely associated with accelerated knee cartilage matrix degradation, which is the main characteristic of OA [6, 7]. It has been suggested that the production of matrix metalloproteinases (MMPs), which degrade cartilage matrix under inflammatory conditions, increases the degradation of the extracellular matrix. It is widely accepted that the breakdown of the extracellular matrix by different MMPs is a characteristic feature of cartilage degeneration in OA that is closely related to the occurrence of OA [10,11,12]. Previous studies have shown that matrix metalloproteinase (MMP) 8 and MMP9 were upregulated in patients with diabetic OA. Their regulatory functions and mechanisms in diabetic OA are not fully understood

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Conclusion