The adipokine lipocalin-2 in the context of the osteoarthritic osteochondral junction.

Amanda Villalvilla,Gabriel Herrero-Beaumont,Raquel Largo,Adela García-Martín,Rodolfo Gómez,Oreste Gualillo

doi:10.1038/srep29243

Abstract

Obesity and osteoarthritis (OA) form a vicious circle in which obesity contributes to cartilage destruction in OA, and OA-associated sedentary behaviour promotes weight gain. Lipocalin-2 (LCN2), a novel adipokine with catabolic activities in OA joints, contributes to the obesity and OA pathologies and is associated with other OA risk factors. LCN2 is highly induced in osteoblasts in the absence of mechanical loading, but its role in osteoblast metabolism is unclear. Therefore, because osteochondral junctions play a major role in OA development, we investigated the expression and role of LCN2 in osteoblasts and chondrocytes in the OA osteochondral junction environment. Our results showed that LCN2 expression in human osteoblasts and chondrocytes decreased throughout osteoblast differentiation and was induced by catabolic and inflammatory factors; however, TGF-β1 and IGF-1 reversed this induction. LCN2 reduced osteoblast viability in the presence of iron and enhanced the activity of MMP-9 released by osteoblasts. Moreover, pre-stimulated human osteoblasts induced LCN2 expression in human chondrocytes, but the inverse was not observed. Thus, LCN2 is an important catabolic adipokine in osteoblast and chondrocyte metabolism that is regulated by differentiation, inflammation and catabolic and anabolic stimuli, and LCN2 expression in chondrocytes is regulated in a paracrine manner after osteoblast stimulation.

Highlights

Obesity and osteoarthritis (OA) form a vicious circle in which obesity contributes to cartilage destruction in OA, and OA-associated sedentary behaviour promotes weight gain
Because osteoblasts from OA subchondral bone exhibit altered differentiation[12], we investigated the expression of LCN2 during osteoblast differentiation
Because LCN2 expression is highly induced in the absence of this stimulus[24], we investigated whether IGF-1 and TGF-β1, two bone anabolic factors often related to OA pathophysiology and PCR (B)

Summary

Introduction

Obesity and osteoarthritis (OA) form a vicious circle in which obesity contributes to cartilage destruction in OA, and OA-associated sedentary behaviour promotes weight gain. OA is the most common rheumatic disease and is characterized by progressive degradation of the articular cartilage[3] and by severe alterations such as loss of joint architecture, pain, and disability, which significantly contribute to sedentary behaviour[1] This sedentary lifestyle is a well-known factor associated with weight gain and obesity[2], which enhances cartilage degradation due to mechanical joint overload[4] and altered metabolism[4], including dysregulated adipokine production[5]. OA joint inflammation is mediated, in part, by innate immune responses elicited by molecules such as interleukin-1 beta (IL-1β) and Toll-like receptor 4 (TLR4) agonists (host-derived molecules generated upon tissue damage)[11] The activities of these molecules affect both the articular cartilage and the subchondral bone[11,12] and are associated with cartilage degradation[11,13], changes in osteoblast phenotype[11,14], and alterations in the www.nature.com/scientificreports/. The crosstalk between these tissues has been investigated, a limited number of in vitro mechanistic studies have been performed, and the precise factors involved in the molecular crosstalk between chondrocytes and osteoblasts are poorly understood

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Conclusion