RIP1 Perturbation Induces Chondrocyte Necroptosis and Promotes Osteoarthritis Pathogenesis via Targeting BMP7.

Jin Cheng,Yingfang Ao,Xin Fu,Xin Zhang,Xiaoning Duan,Xiaoqing Hu,Peng Yang,Chenxi Cao,Qi Li,Jiying Zhang,Yanfang Jiang

doi:10.3389/fcell.2021.638382

Abstract

Osteoarthritis (OA) is a highly prevalent and debilitating joint disorder that characterized by progressive destruction of articular cartilage. There is no effective disease-modifying therapy for the condition due to limited understanding of the molecular mechanisms on cartilage maintenance and destruction. Receptor-interacting protein kinase 1 (RIP1)-mediated necroptosis plays a vital role in various diseases, but the involvement of RIP1 in OA pathogenesis remains largely unknown. Here we show that typical necrotic cell morphology is observed within human OA cartilage samples in situ, and that RIP1 is significantly upregulated in cartilage from both OA patients and experimental OA rat models. Intra-articular RIP1 overexpression is sufficient to induce structural and functional defects of cartilage in rats, highlighting the crucial role of RIP1 during OA onset and progression by mediating chondrocyte necroptosis and disrupting extracellular matrix (ECM) metabolism homeostasis. Inhibition of RIP1 activity by its inhibitor necrostatin-1 protects the rats from trauma-induced cartilage degradation as well as limb pain. More importantly, we identify bone morphogenetic protein 7 (BMP7) as a novel downstream target that mediates RIP1-induced chondrocyte necroptosis and OA manifestations, thereby representing a non-canonical regulation mode of necroptosis. Our study supports a model whereby the activation of RIP1-BMP7 functional axis promotes chondrocyte necroptosis and subsequent OA pathogenesis, thus providing a new therapeutic target for OA.

Highlights

Osteoarthritis (OA) is the most common joint disease, which is a major source of pain, disability, and socioeconomic cost worldwide (Hunter et al, 2014; Safiri et al, 2020)
We provide the first in situ evidence that typical morphological features of necroptosis occur in chondrocytes within osteoarthritic human cartilage, and demonstrate that the expression level of Receptor-interacting protein kinase 1 (RIP1) is significantly upregulated in cartilage from both OA patients and experimental OA rat models
To explore whether chondrocyte necrosis existed in human OA cartilage, Evans blue dye (EBD) uptake of the chondrocytes within freshly obtained cartilage tissues of OA patients and healthy donors was determined in situ by confocal microscopy

Summary

Introduction

Osteoarthritis (OA) is the most common joint disease, which is a major source of pain, disability, and socioeconomic cost worldwide (Hunter et al, 2014; Safiri et al, 2020). RIP1-BMP7 Functional Axis in Osteoarthritis novel molecular mechanisms of cartilage maintenance and destruction is likely to yield new therapeutic strategies for OA. Previous studies mainly focused on chondrocyte apoptosis rather than necrosis, which has long been regarded as an unregulated form of passive cell death and cannot be used as a therapeutic target (Ryu et al, 2012; Hosseinzadeh et al, 2016). Necroptosis is mediated by necrosome, a supermolecular complex which contains receptor-interacting protein kinase 1 and 3 (RIP1, RIP3), and its direct substrate mixed-lineage kinase domain-like protein (MLKL), targeting the complex to appropriate downstream effectors in the necroptosisinducing process (Cho et al, 2009; He et al, 2009; Wang et al, 2014). Given the fact that RIP1 functions upstream of RIP3 and MLKL, it is likely that RIP1 might be a more effective therapeutic target for clinical treatment of OA

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