Upregulation of Bone Morphogenetic Protein-2 Synthesis and Consequent Collagen II Expression in Leptin-stimulated Human Chondrocytes.

Kuo-Chin Huang,Fang-Yao Chiu,Cheng Allen Chang,Yu-Ping Su,Hsing-Chun Kuo,Yan Chen,Shun-Fu Chang,Rong-Ze Hsieh,Cheng-Nan Chen

doi:10.1371/journal.pone.0144252

Abstract

Bone morphogenetic proteins (BMPs) play positive roles in cartilage development, but they can barely be detected in healthy articular cartilage. However, recent evidence has indicated that BMPs could be detected in osteoarthritic and damaged cartilage and their precise roles have not been well defined. Extremely high amounts of leptin have been reported in obese individuals, which can be associated with osteoarthritis (OA) development. The aim of this study was to investigate whether BMPs could be induced in human primary chondrocytes during leptin-stimulated OA development and the underlying mechanism. We found that expression of BMP-2 mRNA, but not BMP-4, BMP-6, or BMP-7 mRNA, could be increased in human primary chondrocytes under leptin stimulation. Moreover, this BMP-2 induction was mediated through transcription factor-signal transducer and activator of transcription (STAT) 3 activation via JAK2-ERK1/2-induced Ser727-phosphorylation. Of note, histone deacetylases (HDACs) 3 and 4 were both involved in modulating leptin-induced BMP-2 mRNA expression through different pathways: HDAC3, but not HDAC4, associated with STAT3 to form a complex. Our results further demonstrated that the role of BMP-2 induction under leptin stimulation is to increase collagen II expression. The findings in this study provide new insights into the regulatory mechanism of BMP-2 induction in leptin-stimulated chondrocytes and suggest that BMP-2 may play a reparative role in regulating leptin-induced OA development.

Highlights

Bone morphogenetic proteins (BMPs) were originally identified by their unique ability to induce ectopic bone and cartilage formation in vivo [1,2]
We examined whether leptin induces BMP expression in human primary chondrocytes
Cells were kept as controls or treated with leptin (5 ng/ml) for 1, 4, 8, and 24 h, and their expression of BMP-2, BMP-4, BMP-6 and BMP-7 mRNA was examined

Summary

Introduction

Bone morphogenetic proteins (BMPs) were originally identified by their unique ability to induce ectopic bone and cartilage formation in vivo [1,2]. BMPs bind and signal through their specific receptors and phosphorylate Smad1/5 to stimulate the expressions of target genes [2]. It has been shown that BMP-2/4 can barely be detected in healthy articular cartilage, but it is highly expressed in osteoarthritic cartilage and joints that have suffered mechanical injury by both chondrocytes and synovial cells, possibly resulting in anabolic development in chondrocytes and/or the formation of osteophytes [2,3,4,5,6,7]. These studies indicate that BMP might play important role in the control of cartilage structure and composition during injury. The precise roles and detailed mechanisms of BMP induction in damaged cartilage have not been taken into account

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