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Aging and Disease    2017, Vol. 8 Issue (5) : 570-582     DOI: 10.14336/AD.2017.0201
Review |
The Pathogenesis of Ossification of the Posterior Longitudinal Ligament
Liang Yan1,Rui Gao2,Yang Liu1,Baorong He1,*,Shemin Lv3,Dingjun Hao1,*
1Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Xi’an, 710054, China
2Department of Respiration, The Children’s Hospital of Xi’an City, Xi’an, 710054, China
3Xi’an Jiaotong University College of Medicine, Xi’an, 710054, China
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Abstract  

Ossification of the posterior longitudinal ligament (OPLL) is a multi-factorial disease involving an ectopic bone formation of spinal ligaments. It affects 0.8-3.0% aging Asian and 0.1-1.7% aging European Caucasian. The ossified ligament compresses nerve roots in the spinal cord and causes serious neurological problems such as myelopathy and radiculopathy. Research in understanding pathogenesis of OPLL over the past several decades have revealed many genetic and non-genetic factors contributing to the development and progress of OPLL. The characterizations of aberrant signaling of bone morphogenetic protein (BMP) and mitogen-activated protein kinases (MAPK), and the pathological phenotypes of OPLL-derived mesenchymal stem cells (MSCs) have provided new insights on the molecular mechanisms underlying OPLL. This paper reviews the recent progress in understanding the pathophysiology of OPLL and proposes future research directions on OPLL.

Keywords Heterotopic ossification      OPLL      BMP      TGF-β      Mesenchymal stem cells      MAPK     
Corresponding Authors: Baorong He,Dingjun Hao   
Just Accepted Date: 07 February 2017   Issue Date: 26 September 2017
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Liang Yan
Rui Gao
Yang Liu
Baorong He
Shemin Lv
Dingjun Hao
Cite this article:   
Liang Yan,Rui Gao,Yang Liu, et al. The Pathogenesis of Ossification of the Posterior Longitudinal Ligament[J]. A&D, 2017, 8(5): 570-582.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0201     OR     http://www.aginganddisease.org/EN/Y2017/V8/I5/570
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[105] Kobashi et al, 2008vitamin D receptor (VDR)N.A.
[27] Horikoshi et al, 2006transforming growth factor-beta3 (TGF-beta3)rs226862rs22847
Table 1  Summary of OPLL susceptibility genes
Figure 1.  BMP/TGF-β signaling and negative regulation in osteoblastogenesis

BMP or TGF-β binds to and activates their receptor type II (RII) and receptor type I (RI) and leads to subsequent phosphorylation of Smads. Activated Smads form a complex with Smad4, translocate into the nucleus and trigger transcription of Runx2. Subsequently, Smads/Smad4 associate with Runx2 to regulate target genes necessary for osteoblastogenesis. BMP/TGF-β signaling can also activate transforming growth factor beta-activated kinase 1 (TAK1) and result in activation of MAPK, leading to enhancement of Smads/Smad4 induced transcription. The negative regulations include prevention of activation of Smads by Smad6/7, inhibition of receptors activation by Smurf and FK506 binding protein 1A (FKBP12), and inhibition of BMPs binding to their receptors by Noggin/Chordin. P, phosphorylation.

Figure 2.  Hypothetic pathogenesis of OPLL. Aberrant activation of BMP and TGF-β signaling plays a central role in development of OPLL

Many pathological alterations, including mechanical stress, inflammatory response, transcriptional and pathway negative regulations, and genetic mutations, can cause activation of BMP and TGF-β signaling. As a result, Smads/Smad4 and MAPK are upregulated and transcriptions of Sox9, Runx2 and Osterix are increased, which modulates the differentiation and proliferation of MSCs, osteoblasts and chondrocytes and ultimately causes OPLL formation and advancement.

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