Sox9 Potentiates BMP2-Induced Chondrogenic Differentiation and Inhibits BMP2-Induced Osteogenic Differentiation

Junyi Liao,Chen Zhao,Weike Si,Wei Huang,Tingxu Fan,Hong Chen,Qiang Cheng,Zhong Yang,Cheng Chen,Nian Zhou,Yongming Zeng,Shixiong Yi,Wei Xu,Liangbo Lin,Ning Hu,Wei Bao,Xi Liang

doi:10.1371/journal.pone.0089025

Abstract

Bone morphogenetic protein 2 (BMP2) is one of the key chondrogenic growth factors involved in the cartilage regeneration. However, it also exhibits osteogenic abilities and triggers endochondral ossification. Effective chondrogenesis and inhibition of BMP2-induced osteogenesis and endochondral ossification can be achieved by directing the mesenchymal stem cells (MSCs) towards chondrocyte lineage with chodrogenic factors, such as Sox9. Here we investigated the effects of Sox9 on BMP2-induced chondrogenic and osteogenic differentiation of MSCs. We found exogenous overexpression of Sox9 enhanced the BMP2-induced chondrogenic differentiation of MSCs in vitro. Also, it inhibited early and late osteogenic differentiation of MSCs in vitro. Subcutaneous stem cell implantation demonstrated Sox9 potentiated BMP2-induced cartilage formation and inhibited endochondral ossification. Mouse limb cultures indicated that BMP2 and Sox9 acted synergistically to stimulate chondrocytes proliferation, and Sox9 inhibited BMP2-induced chondrocytes hypertrophy and ossification. This study strongly suggests that Sox9 potentiates BMP2-induced MSCs chondrogenic differentiation and cartilage formation, and inhibits BMP2-induced MSCs osteogenic differentiation and endochondral ossification. Thus, exogenous overexpression of Sox9 in BMP2-induced mesenchymal stem cells differentiation may be a new strategy for cartilage tissue engineering.

Highlights

From degenerative disorders to traumatic injuries, cartilaginous pathologies present a very significant clinical challenge to the medical fraternity especially due to its lack of regenerative capabilities [1]
We demonstrated here that exogenous overexpression of Sox9 significantly enhanced Bone morphogenetic protein 2 (BMP2)-induced chondrogenic differentiation and cartilage formation, while it inhibited BMP2-induced osteogenic differentiation and endochondral ossification
Overexpression of Sox9 in BMP2 induced chondrogenic differentiation may result in stable chondrogenic phenotype of mesenchymal stem cells (MSCs)

Summary

Introduction

From degenerative disorders to traumatic injuries, cartilaginous pathologies present a very significant clinical challenge to the medical fraternity especially due to its lack of regenerative capabilities [1]. To overcome this drawback, many surgical interventions were applied. The bone marrow stimulation techniques such as microfracture and drilling produce fibrocartilage with insufficient long-term effects [5,6] Restoration techniques such as autologous chondrocyte implantation and osteochondral allograft were limited by insufficient cell supply, damage to the donor site, and immunological reactions [7,8]. Stem cell based and gene-enhanced tissue engineering cartilage is considered to be more promising in the treatment of cartilaginous pathologies [7,9]

Methods

Results

Conclusion