Role of cadherin 2 in the intervertebral disc

Abstract

Intervertebral disc (IVD) degeneration could lead to many serious complications including low back pain and disc herniation. However, the mechanism of disc degeneration is not fully understood, hindering the development of the therapeutics to cure this disease. The integrity of the nucleus pulposus (NP), which is derived from the notochord and situated in the core of the IVD, has long been implicated in the function and homeostasis of the IVD. Previous puncture-induced disc degeneration mouse model showed segregation of NP cell mass during the early stage of disc degeneration, indicating that an alteration in the cell adhesion molecule activities is involved in this process. By microarray analysis, our group have revealed specific expression of Cdh2 gene, encoding cadherin 2/N-cadherin, a subtype of cadherins in the NP cells, suggesting a regulatory role of cadherin 2 in the IVD. Cadherins are single transmembrane glycoproteins mediating calcium-dependent intercellular adhesions. Cadherin 2 is involved in chondrogenesis and skeletogenesis, suggesting that it is important in skeletal development and function.

This study hypothesized that cadherin 2 is required in the normal IVD development and homeostasis. The purposes of this project is firstly to fully characterize changes in cadherin 2 expression in the normal and degenerative discs in rodent and human, and secondly to examine the effect of loss of function of cadherin 2 on IVD homeostasis by functional blocking of the protein in the rodent NP and conditional knock out of cadherin 2 from the murine NP.

The rodent adult NP is similar to human fetal NP, where cadherin 2 is homogeneously expressed in the cell membranes of the notochordal (NC) cells, suggesting that cadherin 2 is a potential NC cell marker. The rodent degenerative NP is similar to human adult NP, where down-regulation of cadherin 2 is observed, the NC cells are replaced by small round cells, and the cell-cell contact is lost. Blocking cadherin 2 function in the rodent NP and conditional knock out of cadherin 2 in the notochord and consequently the NP will lead to transformation of NC cells into small cells, loss of cell-cell contact and a change in the extracellular matrix (ECM), suggesting that cadherin 2 is important in the maintenance of the phenotype and intercellular adhesion of the NC cells.

In conclusion, this study indicates that cadherin 2 is mainly expressed in the NC cells of the NP and serves as a potential NC cell marker. It plays a regulatory role in the IVD homeostasis through the maintenance of the NC cell phenotype by intercellular adhesions. This study contributes to the knowledge about the role of cadherin 2 in the disc homeostasis and the early mechanism of disc degeneration, and this would help in developing a therapeutic method to intervene or even reverse the disease process of disc degeneration.