Lipocalin 2: A New Mechanoresponding Gene Regulating Bone Homeostasis. (February 2015)

• Record Type: Journal Article
• Authors: Rucci, Nadia; Capulli, Mattia; Piperni, Sara Gemini; Cappariello, Alfredo; Lau, Patrick; Frings‐Meuthen, Petra; Heer, Martina; Teti, Anna
• Is Part Of: Journal of bone and mineral research. Volume 30:Number 2(2015:Feb.)
• Page Start: 357
• Page End: 368
• Publication Date: 2015-02
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2341
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2341-sec-0001" sec-type="section"> <p>Mechanical loading represents a crucial factor in the regulation of skeletal homeostasis. Its reduction causes loss of bone mass, eventually leading to osteoporosis. In a previous global transcriptome analysis performed in mouse calvarial osteoblasts subjected to simulated microgravity, the most upregulated gene compared to unit gravity condition was <italic>Lcn2</italic>, encoding the adipokine Lipocalin 2 (LCN2), whose function in bone metabolism is poorly known. To investigate the mechanoresponding properties of LCN2, we evaluated LCN2 levels in sera of healthy volunteers subjected to bed rest, and found a significant time‐dependent increase of this adipokine compared to time 0. We then evaluated the in vivo LCN2 regulation in mice subjected to experimentally‐induced mechanical unloading by (1) tail suspension, (2) muscle paralysis by botulin toxin A (Botox), or (3) genetically‐induced muscular dystrophy (MDX mice), and observed that <italic>Lcn2</italic> expression was upregulated in the long bones of all of them, whereas physical exercise counteracted this increase. Mechanistically, in primary osteoblasts transfected with LCN2‐expression‐vector (OBs‐Lcn2) we observed that <italic>Runx2</italic> and its downstream genes, <italic>Osterix</italic> and <italic>Alp</italic>, were transcriptionally downregulated, and alkaline phosphatase (ALP) activity was less prominent versus empty‐vector transduced osteoblasts (OBs‐empty). OBs‐Lcn2 also exhibited an increase of the <italic>Rankl/Opg</italic> ratio and <italic>IL‐6</italic> mRNA, suggesting that LCN2 could link poor differentiation of osteoblasts to enhanced osteoclast stimulation. In fact, incubation of purified mouse bone marrow mononuclear cells with conditioned media from OBs‐Lcn2 cultures, or their coculture with OBs‐Lcn2, improved osteoclastogenesis compared to OBs‐empty, whereas treatment with recombinant LCN2 had no effect. In conclusion, our data indicate that LCN2 is a novel osteoblast mechanoresponding gene and that its regulation could be central to the pathological response of the bone tissue to low mechanical forces. © 2014 American Society for Bone and Mineral Research</p> </sec> </abstract>