Involvement of bone morphogenic protein‐2 (BMP‐2) in the pathological ossification process of the spinal ligament

Tanaka, Hiroshi; Nagai, Ei; Murata, Hidenori; Tsubone, Tetsu; Shirakura, Yoshiharu; Sugiyama, Toshihiro; Taguchi, Toshihiko; Kawai, Shinya

doi:10.1093/rheumatology/40.10.1163

Cited by 60 publications

(34 citation statements)

References 19 publications

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“…Among them, the role of BMP-2 has definitely been demonstrated in development of OPLL [10,11,23], and ER stress response mediated by PERK-elF2a-ATF4 pathway was proved to be involved in osteoblast differentiation induced by BMP-2 [21]. In this study, treatment of wild-type primary osteoblasts with BMP-2, which is required for osteoblast differentiation, induced ER stress, leading to an increase in ATF4 protein expression levels.…”

Section: Discussionmentioning

confidence: 60%

Upregulated expression of PERK in spinal ligament fibroblasts from the patients with ossification of the posterior longitudinal ligament

et al. 2013

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Purpose Molecular mechanism of ossification of the posterior longitudinal ligament (OPLL) remains unclear. This study was to investigate different expressions of PERK between the spinal ligament fibroblasts from OPLL patients and non-OPLL patients, and demonstrate knockdown of PERK protein expression by RNA interference inhibiting expression of osteocalcin (OCN), alkaline phosphatase (ALP), and type I collagen (COL I) in the cells from OPLL patients. Methods Spinal ligament cells were cultured using tissue fragment cell culture and identified by immunocytochemistry and immunofluorescence. The mRNA expression of osteoblast-specific genes of OCN, ALP and COL I was detected in the cells from OPLL and non-OPLL patients by semiquantitative reverse transcription-polymerase chain reaction. The protein expression of PERK was detected by Western blotting. And then, after 72 h, when RNA interference against PERK was performed on the cells from OPLL patients, expression of the osteoblast-specific genes was compared again between the transfection group and non-transfection group. Results Spinal ligament fibroblasts were observed 7-10 days after cell culture. Immunocytochemistry and immunofluorescence exhibited positive results of vimentin staining. The mRNA expressions of OCN, ALP and COL I and protein expression of PERK in the cells from OPLL patients were significantly greater than those from non-OPLL patients. In addition, knockdown of PERK protein expression inhibited the mRNA expressions of OCN, ALP and COL I remarkably in the transfection group compared with the non-transfection group, at 72 h after RNA interference targeting PERK was performed on the cells from OPLL patients. Conclusions The cultured fibroblasts from OPLL patients exhibited osteogenic characteristics, and PERKmediated ER stress might be involved in development of OPLL.

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Section: Discussionmentioning

confidence: 60%

Upregulated expression of PERK in spinal ligament fibroblasts from the patients with ossification of the posterior longitudinal ligament

et al. 2013

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“…An in vitro study has shown that BMP-2, an importance osteogenic growth factor, induced high ALP activity in normal LFCs from patients without OLF [32]. Previous studies have also reported that BMPs and BMP receptors expressed in ossified ligament tissue from OLF patients and BMP induced OLF in a mice model [8,31].…”

Section: Discussionmentioning

confidence: 95%

“…Histologic study revealed that the developmental mode of OLF was mainly endochondral ossification [1]. In vitro and in vivo studies have indicated that the pathogenesis of OLF was associated with osteogenic differentiation of the spinal ligament cells [30][31][32]. Increased recognition of the nature of OLF has highlighted the importance of determining the molecular mechanisms of osteogenic differentiation of LFCs.…”

Section: Discussionmentioning

confidence: 99%

Growth/differentiation Factor-5 Induces Osteogenic Differentiation of Human Ligamentum Flavum Cells through Activation of ERK1/2 and p38 MAPK

Zhong

Chen

Zhang

et al. 2010

Cell Physiol Biochem

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Ossification of ligamentum flavum (OLF) is a pathological ectopic ossification in the spinal ligament, leading to spinal canal stenosis, but little was known about its pathogenesis. A previous study has found growth/differentiation factor (GDF)-5 expression at ossified sites of the ligaments from OLF patients. This study aimed to investigate the osteogenic effects of GDF-5 on cultured human ligamentum flavum cells (LFCs). LFCs were isolated from human spinal ligamentum flavum, and treated with or without recombinant human (rh) GDF-5. Alkaline phosphatase (ALP) activity was measured. Expression of osteocalcin was assessed by reverse transcriptase-PCR, Western blotting and immunofluorescence. Matrix mineralization was assessed by alizarin red staining. Activation of mitogen-activated protein kinases (MAPK) ERK1/2, p38 and JNK were detected by Western blotting. We found that rhGDF-5 treatment increased ALP activity and osteocalcin expression in a time-and dosedependent manner, and induced mineralized nodule form. In addition, rhGDF-5 challenge mediated the ERK1/2 and p38 activation but not JNK. Inhibiting this activation pharmacologically, using U0126, a ERK1/ 2 inhibitor, or SB203580, a p38 inhibitor, resulted in significantly lower ALP activity and osteocalcin protein expression. The present study shows that rhGDF-5 induces osteogenic differentiation of human LFCs through activation of ERK1/2 and p38 MAPK. These findings give some new insight into the pathogenesis of OLF.

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“…7 Kawaguchi et al 10 initially showed that BMP-2 and TGF-b were present in the ossified matrix of the posterior longitudinal ligaments of patients with OPLL and thus suggested that BMP-2 and TGF-b were important initiators in the ossification process in OPLL. Tanaka et al 35 later confirmed that the BMP-2 gene was expressed in spinal ligaments of patients with pathological ectopic ossification of the spinal ligaments (such as OPLL). Furthermore, they proved that BMP-2 presence activated alkaline phosphatase, which suggested that BMP-2 could have a direct causal role in ossification of spinal ligaments.…”

Section: Cytokines and Transcription Factorsmentioning

confidence: 96%

The genetics of ossification of the posterior longitudinal ligament

Stetler¹,

Marca²,

Park³

2011

FOC

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Object Ossification of the posterior longitudinal ligament (OPLL) is a pathological process of ectopic calcification with a preponderance for the cervical spine. Epidemiological and familial studies have both indicated predisposition; however, the genetic inheritance pattern and responsible genes for OPLL are still uncertain. The aim of this study was to evaluate and summarize the current understanding of the genetics underlying OPLL. Methods The authors reviewed epidemiological and genetic studies surrounding OPLL, with a particular focus on inheritance patterns and potential genes responsible for OPLL, using a PubMed database literature search. Results Despite an unclear inheritance pattern, there appears to be a strong familial link in patients with OPLL. Examination of these patterns using linkage analysis has shown multiple candidate genes that could be responsible for the inheritance of OPLL. Genes for collagen, nucleotide pyrophosphatase, transforming growth factors, and the vitamin D receptor have all been implicated. Additionally, multiple cytokines and growth factors, including bone morphogenetic proteins as well as other proteins and interleukins involved in bone development, have been shown to be abnormally expressed in patients with OPLL. In addition, multiple mechanical and metabolic factors such as hyperinsulinemia and obesity have been shown to be linked to OPLL. Conclusions Ossification of the posterior longitudinal ligament has a complex inheritance pattern. It does not appear that OPLL follows a simple, single-gene Mendelian inheritance pattern. Development of OPLL is more likely multifactorial in nature and develops in patients with a genetic predisposition from a variety of different mutations in various genes on various chromosomes. Additionally, environmental factors and interaction by other pathological disease processes, such as obesity and diabetes mellitus, may play a role in the development of OPLL in susceptible individuals.

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Involvement of bone morphogenic protein‐2 (BMP‐2) in the pathological ossification process of the spinal ligament

Cited by 60 publications

References 19 publications

Upregulated expression of PERK in spinal ligament fibroblasts from the patients with ossification of the posterior longitudinal ligament

Upregulated expression of PERK in spinal ligament fibroblasts from the patients with ossification of the posterior longitudinal ligament

Growth/differentiation Factor-5 Induces Osteogenic Differentiation of Human Ligamentum Flavum Cells through Activation of ERK1/2 and p38 MAPK

The genetics of ossification of the posterior longitudinal ligament

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