Upregulation of lipocalin-2 (LCN2) in osteoarthritic cartilage is not necessary for cartilage destruction in mice

Abstract

Purpose: Lipocalin-2 (LCN2) has recently emerged as a novel adipokines involved in variety of physiological and pathophysiological processes. Although recent in vitro cell-based studies suggest that increased LCN2 level in OA may be detrimental, the precise in vivo role of LCN2 in OA progression has been challenging to define. Here, we performed a set of experiments aimed to elucidate in vivo role of LCN2 in the pathogenesis of OA. Methods: The expression of LCN2 were determined at the mRNA and protein levels in primary cultured mouse chondrocytes and in human and mouse OA cartilage. Experimental OA was induced in wild-type or Lcn2 knockout (KO) mice by destabilization of the medial meniscus (DMM) surgery or intra-articular (IA) injection of adenoviruses expressing HIF-2α (Ad-Epas1), ZIP8 (Ad-Zip8). The effect of LCN2 overexpression on the cartilage of wild-type mice was examined by IA injection of Ad-Lcn2. Primary culture mouse chondrocytes were treated with Lcn2-siRNA or were infected with Ad-Lcn2, and gene expression patterns analyzed by using reverse transcription (RT)-PCR. Results: LCN2 mRNA levels in chondrocytes was markedly increased by the pro-inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor-α (TNF-α), and by previously identified catabolic regulators of OA, such as hypoxia-inducible factor (HIF)-2α and components of the zinc-ZIP8-MTF1 axis. LCN2 protein levels were also markedly increased in human OA cartilage and cartilage from various experimental mouse models of OA. However, overexpression of LCN2 in chondrocytes did not modulate the expression of cartilage matrix molecules or matrix-degrading enzymes. Furthermore, LCN2 overexpression in mouse cartilage via IA injection of Ad-Lcn2 did not cause OA pathogenesis, and Lcn2 KO mice showed no alteration in DMM-induced OA cartilage destruction. Conclusions: Our observation collectively suggest that upregulation of LCN2 in OA cartilage is not sufficient or necessary for OA cartilage destruction in mice.