Imbalance Between Bone Morphogenetic Protein 2 and Noggin Induces Abnormal Osteogenic Differentiation of Mesenchymal Stem Cells in Ankylosing Spondylitis.

Abstract

OBJECTIVE:

To study the osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BM-MSCs) from patients with ankylosing spondylitis (AS) and to investigate the mechanisms of abnormal osteogenic differentiation of BM-MSCs in AS.

METHODS:

BM-MSCs from healthy donors (HD-MSCs) and patients with AS (AS-MSCs) were cultured in osteogenic differentiation medium for 0-21 days, after which their osteogenic differentiation capacity was determined using alizarin red S and alkaline phosphatase assays. Gene expression levels of osteoblastic markers and related cytokines were detected by high-throughput quantitative reverse transcription-polymerase chain reaction. Enzyme-linked immunosorbent assay was performed to detect protein levels of bone morphogenetic protein 2 (BMP-2) and Noggin in the cell culture supernatant. The activation of Smad1/5/8 and MAPK signaling pathways was measured by Western blotting. The balance between BMP-2 and Noggin expression was regulated using lentiviruses encoding short hairpin RNA and exogenous Noggin, respectively, which enabled evaluation of how this balance affected osteogenic differentiation of AS-MSCs.

RESULTS:

AS-MSCs outperformed HD-MSCs in osteogenic differentiation capacity. During osteogenic differentiation, AS-MSCs secreted more BMP-2 but less Noggin, accompanied by an overactivation of Smad1/5/8 and ERK-1/2. When the Noggin concentration was increased or BMP-2 expression was inhibited, the abnormal osteogenic differentiation of AS-MSCs was rectified. In addition, the balance between BMP-2 and Noggin secretion was restored.

CONCLUSION:

The results of this study demonstrate that an imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of AS-MSCs. These findings reveal a mechanism of pathologic osteogenesis in AS and provide a new perspective on inhibiting pathologic osteogenesis by regulating the balance between BMP-2 and Noggin.

• Authors: Zhongyu Xie, Peng Wang, Yuxi Li, Wen Deng, Xin Zhang, Hongjun Su, Deng Li, Yanfeng Wu, Huiyong Shen
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 68 Issue 2 Pg. 430-40 (Feb 2016) ISSN: 2326-5205 [Electronic] United States
• PMID: 26413886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016, American College of Rheumatology.

Chemical References

• BMP2 protein, human
• Bone Morphogenetic Protein 2
• Carrier Proteins
• Cytokines
• SMAD1 protein, human
• SMAD5 protein, human
• SMAD9 protein, human
• Smad1 Protein
• Smad5 Protein
• Smad8 Protein
• noggin protein

Topics

• Blotting, Western
• Bone Morphogenetic Protein 2 (genetics, metabolism)
• Carrier Proteins (genetics, metabolism)
• Case-Control Studies
• Cell Differentiation (genetics)
• Cell Proliferation
• Cytokines (genetics, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Gene Expression Profiling
• Humans
• MAP Kinase Signaling System
• Mesenchymal Stem Cells (cytology, metabolism)
• Osteoblasts (cytology, metabolism)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Smad1 Protein (metabolism)
• Smad5 Protein (metabolism)
• Smad8 Protein (metabolism)
• Spondylitis, Ankylosing (genetics, metabolism)