Dkk1 acts as a negative regulator in the osteogenic differentiation of the posterior longitudinal ligament cells

Abstract

Ossification of the posterior longitudinal ligament (OPLL) is a spinal disorder characterized by progressive ectopic bone formation in the PLL of the spine. Dickkopf‐1 (Dkk1) is a secreted inhibitor of the Wnt pathway that negatively regulates bone formation during skeletal development. However, whether Dkk1 impacts the pathogenesis of OPLL has not been reported. This study is to investigate the role of Dkk1 in the development of OPLL. Our results show that the serum levels of Dkk1 are decreased in OPLL patients compared with non‐OPLL controls. The expression of Dkk1 is also reduced in OPLL ligament cells. Downregulation of Dkk1 in ligament cells is associated with activation of the Wnt/β‐catenin signaling, as indicated by stabilized β‐catenin and increased T‐cell factor‐dependent transcriptional activity. Functionally, Dkk1 exerts a growth‐inhibitory effect by repressing proliferation but promoting apoptosis of ligament cells. Dkk1 also suppresses bone morphogenetic protein 2‐induced entire osteogenic differentiation of ligament cells, and this suppression is mediated via its inhibition of the Wnt pathway. Our results demonstrate for the first time that Dkk1 acts as an important negative regulator in the ossification of the PLL. Targeting the Wnt pathway using Dkk1 may represent a potential therapeutic strategy for the treatment of OPLL.

circSKIL promotes the ossification of cervical posterior longitudinal ligament by activating the JNK/STAT3 pathway

“…OCN is the most abundant non-collagenous protein in bone matrix and has a crucial role in the process of biomineralization during osteogenic maturation ( 25 ). Alterations in the expression levels of these markers are commonly used to identify the osteogenic differentiation level of ligament cells, as previously reported ( 6 , 7 , 26 ). In the present study, circSKIL was overexpressed in control ligament cells to investigate its role in osteogenic differentiation.…”

“…The silencing of lncRNA SNHG1, which is highly expressed in OPLL tissues, significantly inhibited the osteogenic differentiation of ligament fibroblastic cells ( 6 ). Dickkopf-1 (Dkk1) is a secreted inhibitor of the Wnt pathway, and its expression level was significantly decreased in OPLL patients and ligament cells compared with that in non-OPLL controls ( 7 ). Treatment with recombinant Dkk1 markedly reversed the osteogenic differentiation of OPLL ligament cells via inhibition of the Wnt pathway ( 7 ).…”

“…Dickkopf-1 (Dkk1) is a secreted inhibitor of the Wnt pathway, and its expression level was significantly decreased in OPLL patients and ligament cells compared with that in non-OPLL controls ( 7 ). Treatment with recombinant Dkk1 markedly reversed the osteogenic differentiation of OPLL ligament cells via inhibition of the Wnt pathway ( 7 ). In addition, microRNA (miRNA/miR)-563 levels were found to be significantly higher in OPLL ligament cells, and the silencing of miR-563 considerably inhibited the osteogenic differentiation of OPLL ligament cells ( 8 ).…”