Multifaceted signaling regulators of chondrogenesis: Implications in cartilage regeneration and tissue engineering

Jordan D Green, Viktor Tollemar, Mark Dougherty, Zhengjian Yan, Liangjun Yin, Jixing Ye, Zachary Collier, Maryam K Mohammed, Rex C Haydon, Hue H Luu, Richard Kang, Michael J Lee, Sherwin H Ho, Tong-Chuan He, Lewis L Shi, Aravind Athiviraham, Jordan D Green, Viktor Tollemar, Mark Dougherty, Zhengjian Yan, Liangjun Yin, Jixing Ye, Zachary Collier, Maryam K Mohammed, Rex C Haydon, Hue H Luu, Richard Kang, Michael J Lee, Sherwin H Ho, Tong-Chuan He, Lewis L Shi, Aravind Athiviraham

Abstract

Defects of articular cartilage present a unique clinical challenge due to its poor self-healing capacity and avascular nature. Current surgical treatment options do not ensure consistent regeneration of hyaline cartilage in favor of fibrous tissue. Here, we review the current understanding of the most important biological regulators of chondrogenesis and their interactions, to provide insight into potential applications for cartilage tissue engineering. These include various signaling pathways, including: fibroblast growth factors (FGFs), transforming growth factor β (TGF-β)/bone morphogenic proteins (BMPs), Wnt/β-catenin, Hedgehog, Notch, hypoxia, and angiogenic signaling pathways. Transcriptional and epigenetic regulation of chondrogenesis will also be discussed. Advances in our understanding of these signaling pathways have led to promising advances in cartilage regeneration and tissue engineering.

Keywords: BMPs; Cartilage; Cell signaling; Chondrogenesis; FGF; Hedgehog; Regenerative medicine; Sox9; TGFβ; Wnt.

Figures

Figure 1
Figure 1
Currently hypothesized lineage-specific differentiation of mesenchymal stem cells (MSCs). Upon receiving appropriate differentiation cues, MSCs are multipotent stem cells and may undergo a cascade of differentiation stages, including progenitor proliferation and expansion, lineage commitment and progression, differentiation and maturation, and subsequently differentiate into multiple types of tissues, such as bone, cartilage, fat, msulce, tendon, etc. It remains a challenge to direct MSCs to differentiate into a specific type of cells/tissues. Furthermore, it is not well understood how early different lineages diverge from MSCs. Nonetheless, MSCs represent one of the most promising populations of progenitors for regenerative medicine and tissue engineering.
Figure 2
Figure 2
Marker/regulator gene expression in different zones of the growth plate and the perichondrium. The important and representative marker genes are listed.
Figure 3
Figure 3
Currently identified regulators of chondrogenic differentiation from MSCs. Currently reported signaling molecules, transcription factors, microRNAs and other regulators are listed. Positive regulators are shown on the top panel in green, while the inhibitory regulators are shown in red at the bottom panel.

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