Research Article: The Pathogenesis of Ossification of the Posterior Longitudinal Ligament

Date Published: October 1, 2017

Publisher: JKL International LLC

Author(s): Liang Yan, Rui Gao, Yang Liu, Baorong He, Shemin Lv, Dingjun Hao.


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.

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OPLL has a strong genetic predisposition. Familial OPLL cases have been reported in both Asian and Caucasian. The associated genetic loci linked to OPLL susceptibility have been identified. For example Terayama et al have reported that the prevalence of OPLL is 26% in the parents and 29% in the siblings of probands from 347 OPLL families, which is significantly higher than that in the general population [18]. Matsunaga et al found that the prevalence of OPLL is higher in the sibs sharing identical human leukocyte antigen (HLA) haplotypes from families of 24 OPLL patients. Later on, a non-parametric linkage analysis focusing on the HLA region revealed a significant linkage on D6S276 with OPLL [19]. Some candidate genes were identified around the marker, including collagen 11A2 (COL11A2) and retinoic X receptor beta (RXRB). Another significant linkage is D21S1903 on 21q showing collagen 6A1 (COL6A1) as a potential genetic factor to OPLL [20].

Besides linkage studies and GWAS, many target gene association studies of OPLL have been carried out over the past several decades. Numerous genes, including cytokines and growth factors, have been revealed as potential factors that contribute to the pathophysiology of OPLL, which are listed in table 1. Many candidates reside in the functional positions that have been defined by linage studies or GWAS above. In the meantime, in vitro and in vivo expression profile analysis has suggested multiple signaling pathways involved in the development and progression of OPLL, including transforming growth factor-beta (TGF-β), bone morphogenetic protein (BMP) and mechanical stress signaling. Here we focus on several major OPLL-associated candidate genes and their signaling pathways.

MSCs are multipotent progenitor cells that can differentiate into a variety of cell types, including osteoblasts and chondrocytes. MSCs have been reported to play important roles in pathogenic development of several ossification process, such as fibrodysplasia ossificans progressiva (FOP) [69], ectopic ossification following burn injury[70] and aortic valve calcification [71]. The initial attempt to isolate MSCs from human spinal ligaments was made by Asari et al. They found these MSCs have potentials to differentiate into osteogenic, adipogenic or chondrogenic cells with expressions of surface markers of CD34, 73, 90 and 105 but not CD45. They located in the collagenous matrix of the ligament and perivascular areas [72]. Further study showed that MSCs with perivascular residing expressed pericytes marker α-smooth muscle actin (α-SMA) but not endothelial marker CD31, thus was a subpopulation of pericytes. This is coincident with the theory that a subset of pericytes was MSCs. The ossified ligamentum flavum (OLF) showed a significant higher quantity of MSCs around blood vessels and within collagenous matrix as compared to non-OLF samples [73]. OPLL-derived MSCs showed significantly higher osteogenic differentiation potential and in vitro increases in activity of ALP and expressions of BMP2, runt-related transcription factor 2 (Runx2) and ALP than those from non-OPLL patients. The author suggested that an upregulation of osteogenic differentiation potential of OPLL-derived MSCs could be a causal factor to the ossification in spinal ligaments [74].

Sclerostin and dickkopf-1(DKK1) are Wnt/β-catenin signal antagonists that play an important role in bone formation. Sclerostin level reflects age-related changes in bone mass and turnover rate [81]. The secretion of sclerostin increases from individual osteocytes with aging [82]. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass [83]. Serum sclerostin levels in the male OPLL subjects group are significantly higher than those in the control group, which is positively correlated with age and bone mineral density of total hip (TH-BMD). Serum sclerostin and DKK1 levels are negatively correlated in male OPLL subjects. Systemic secretion of sclerostin also increases with advancing age and with higher bone mass in male OPLL subjects [84].

Many attempts have been made to identify both genetic and environmental factors that cause OPLL. The recent GWAS analysis based on large-scale samples have significantly narrowed the functional positions on the chromosomes that may harbor the causal genes of OPLL. However, more efficient methods and statistical analysis are required to identify the target genes from these regions. Although a number of OPLL susceptibility genes have been revealed with appearance of specific SNPs in OPLL specimens for over several decades, most studies are based on small sample sizes and small number of examined sequence variants. Thus, a systematic SNP characterization in OPLL tissues based on large scale samples using whole genome or exome next generation sequencing method will be helpful to close this gap. In addition, lack of further functional characterizations of these SNPs makes the genetic association studies insufficient. Whether the SNPs identified to be associated with OPLL are non-functional consequences from the development and progression of OPLL or the causes to the disease remains to be determined.




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