Osteoarthritis (OA) is an age-dependent, chronic, incurable, and destructive joint disease characterized by degradation of cartilage, hypertrophy of chondrocyte, and sclerosis of subchondral bone [
1] and is a main cause of pain and disability of older individuals [
2]. It seems that no pharmacological agents could prevent and treat OA, and alleviating joint pain could be the only medical option for OA, which is often unsuccessful, leading to total joint replacement [
3,
4]. The lack of treatment may be ascribed to the unclear etiology of OA.
Articular cartilage is a highly specialized connective tissue with an avascular structure. However, cartilage loses the ability to stay avascular in the osteoarthritic environment [
5], indicating that angiogenesis could contribute to the pathogenesis of OA. Previous researches found the contribution of angiogenesis of osteophyte formation in OA [
6]. Angiogenesis is closely associated with the pathogenesis of OA [
7]. Neovascularization modulates chondrocyte functions and contributes towards abnormal tissue growth and perfusion, ossification, and endochondral bone development [
8] and leads to oxidative stress and inflammation, which results to matrix degradation [
9]. Angiogenesis is regulated by a delicate balance between endogenous angiogenic and anti-angiogenic factors. It has been demonstrated that Netrin-1 (NT-1) is the factor regulating patterning of the vascular system [
10], and NT-1 induced proliferation, migration, and tube formation of endothelial cells and human aortic smooth muscle cells, via Netrin-1 receptor DCC (Deleted in Colorectal Cancer) [
11]. The vascular endothelial growth factor (VEGF) might contribute to the angiogenesis of NT-1/DCC [
12]. VEGF plays a key role of angiogenesis in the pathogenesis of OA and is essential for establishing epiphyseal vascularization and remodeling hypertrophic cartilage, which finally leads to endochondral bone formation [
13]. Whether or not NT-1/DCC and VEGF interact in regulating angiogenesis of OA cartilage is not known. And the upstream signaling that regulates NT-1/DCC-VEGF to angiogenesis in cartilage is still unclear.
Early growth response-1 (Egr-1), also called NGFI-A, is a zinc finger transcription factor and immediate early gene, which plays an important role in angiogenesis [
14,
15]. Meanwhile, Egr-1 may be involved in the pathogenesis of OA [
16,
17]. Few studies report the effect of Egr-1 to angiogenesis in osteoarthritic cartilage. Thus, our present study provides a mechanism by which Egr-1 induced angiogenesis via NT-1/DCC-VEGF pathway.