Overexpression of TIMP3 inhibits discogenic pain by suppressing angiogenesis and the expression of substance P in nucleus pulposus

Abstract

Approximately 50% of the cases of low back pain (LBP) are attributed to discogenic origin. The causes of discogenic pain are complicated and consist of a complex biochemical cascade. Neovascularization of intervertebral discs (IVDs) is believed to be associated with discogenic pain. The anti-angiogenesis ability of tissue inhibitor of metalloproteinase-3 (TIMP3) has been reported in many tumors, yet whether TIMP3 is associated with neovascularization of IVDs remains unknown. In the present study, both in vitro and in vivo models were used to investigate the association between discogenic pain and TIMP3 expression in nucleus pulposus (NP). PCR results demonstrated that inflammation induced downregulation of TIMP3 expression in NP cells. By using an adenovirus system to upregulate TIMP3 expression, the effect of TIMP3 on angiogenesis was measured by endothelial cell migration and tube formation assays. The results demonstrated that overexpression of TIMP3 suppressed angiogenesis in NP without the regulation of vascular endothelial growth factor (VEGF) expression. TNF-α converting enzyme (TACE) expression was downregulated by TIMP3, thus inhibiting the TACE-induced activation of TNF-α in NP cells. Immunohistochemical staining of IVDs also confirmed that TIMP3 inhibited the expression of substance P in NP. Taken together, the present results indicated the expression of TIMP3 in NP may have a key role in the development of discogenic pain.