FoxC2 Enhances BMP7-Mediated Anabolism in Nucleus Pulposus Cells of the Intervertebral Disc

Abstract

Bone-morphogenetic protein-7 (BMP-7) is a growth factor that plays a major role in mediating anabolism and anti-catabolism of the intervertebral disc matrix and cell homeostasis. In osteoblasts, Forkhead box protein C2 (FoxC2) is a downstream target of BMPs and promotes cell proliferation and differentiation. However, the role FoxC2 may play in degenerative human intervertebral disc tissue and the relationship between FoxC2 and BMP-7 in nucleus pulposus (NP) cells remain to be elucidated. This study aims to investigate the presence and signaling mechanisms of FoxC2 in degenerative human intervertebral disc tissue and NP cells. Western blot and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses were used to measure FoxC2 expression in the NP tissue and cells. Transfections were carried out to measure the effect of FoxC2 on BMP-7-mediated extracellular matrix upregulation. Adenoviral knock-down of Smad1 was performed to investigate the mechanism of BMP-7-induced FoxC2 expression. In degenerative NP tissue, FoxC2 was markedly upregulated and positively correlated with increased disc degeneration. Induction of NP cell proliferation was confirmed by using cell counting kit-8 assay, immunocytochemistry and real-time qRT-PCR for Ki67. FoxC2 led to decreased noggin expression and increased Smad1/5/8 phosphorylation. During combined treatment with BMP-7, FoxC2 greatly potentiated anabolism through synergistic mechanisms on ECM formation. Combination therapy using BMP-7 and FoxC2 may be beneficial to the treatment of intervertebral disc degeneration.

Foxc2 and BMP2 Induce Osteogenic/Odontogenic Differentiation and Mineralization of Human Stem Cells from Apical Papilla

“…In myoblasts, decreased endogenous Foxc2 reduced cell proliferation activity, while increased expression of Foxc2 promoted cell proliferation [ 13 ]. In osteoblasts, upregulated Foxc2 facilitates cell proliferation in vitro [ 32 ], and Foxc2 might encourage the survival and proliferation of osteoblasts by upregulating integrin β 1 [ 11 ]. Consistent with the previous reports [ 13 , 32 ], our data showed that the proliferation of Foxc2 gene-transfected SCAP was slightly stronger than that of the other three groups.…”

“…In osteoblasts, upregulated Foxc2 facilitates cell proliferation in vitro [ 32 ], and Foxc2 might encourage the survival and proliferation of osteoblasts by upregulating integrin β 1 [ 11 ]. Consistent with the previous reports [ 13 , 32 ], our data showed that the proliferation of Foxc2 gene-transfected SCAP was slightly stronger than that of the other three groups. However, the proliferative activity of Foxc2 and BMP2 double gene-transfected SCAP was reduced on day 8, which implies that Foxc2 and BMP2 synergistically control the proliferation of SCAP.…”

Are specific gene expressions of extracellular matrix and nucleus pulposus affected by primer cell cultures prepared from intact or degenerative intervertebral disc tissues?

“…In a similar study, Wang et al used a qRT-PCR methodology (29). They reported that bone morphogenetic factor-7 played an essential role in cell hemostasis and in regulating the anabolism and catabolism of intervertebral discs.…”

Anticancer effects of oridonin on colon cancer are mediated via BMP7/p38 MAPK/p53 signaling

“…BMP7 is a pleiotropic cytokine which transforms mesenchymal cells into bone and cartilage. Owing to its osteogenic activity, BMP7 has been approved by the FDA for the treatment of bone-related diseases, such as spinal fusion and bone fracture healing (36,37). BMP7 has also been implicated in tumors, such as prostate and breast cancer (38,39).…”