Nanomedicine-Driven Approaches for Kartogenin Delivery: Advancing Chondrogenic Differentiation and Cartilage Regeneration in Tissue Engineering

Abstract

Articular cartilage degradation and osteocartilage defects are the most prevalent concerns that vary from localized to more systemic forms of cartilage disease. However, regulating chondrogenic differentiation within the joints remains a significant challenge. Kartogenin, a small heterocyclic compound, has recently garnered considerable attention as a potential therapeutic agent, owing to both chondrogenic and chondroprotective properties for intra-articular therapy. Initially, it was created for osteoarthritis; it has also been used to address various diseased conditions, such as the regeneration of disc and bone-tendon junctions. On top of that, it preserves the equilibrium between cartilage catabolism and anabolism, while also mitigating inflammation and alleviating pain by preventing damage induced by cytokines. To modulate tissue function and cellular behaviour, it is crucial to have sustained release of ketogenic through an appropriate delivery system. A multitude of biomaterial-based carriers have been developed for the prolonged release of kartogenin. Moreover, many biological mechanisms of action of kartogenin have been identified. The most critical molecular mechanism among them is the dissociation of filamin A from core-binding factor (CBF)-β induced by kartogenin. Filamin A subsequently translocates to the nucleus, where it engages with RUNX-1 to transcribe genes implicated in the chondrogenesis of mesenchymal stem cells. This review focuses on the development of biomaterials functionalized with kartogenin, including their structure, design, physicochemical properties, biological roles, molecular mechanisms of action, and applications in tissue engineering and regenerative medicine. In conclusion, we discussed the future possibilities and challenges posed by recent advancements in kartogenin research and their potential applications in tissue regeneration.

Keywords: Kartogenin; TGF-β; cartilage regeneration; chondrogenesis; osteoarthritis.

Figure 1

Mechanism of chondrocytes proliferation and differentiation. Data from Park et al.

Figure 2

The chemical structure of KGN.

Figure 3

Schematic diagram of KGN molecular mechanism of action by the Filamin A/CBFβ/RUNX-1 Pathway. Data from Marini et al.

Figure 4

Molecular mechanism of KGN induced Hippo/TAOK1 Signalling Pathway. Adapted from Fu M, Hu Y, Lan T, Guan KL, Luo T, Luo M. The Hippo signalling pathway and its implications in human health and diseases. Signal Transduct Target Ther. 2022;7(1):376. Copyright © 2022, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License.

Figure 5

(a) AKT/P13K Signalling Pathway, (b) The molecular mechanism of KGN induced Smad/TGF-β Pathway, and (c) IL-6/Stat3 Pathway.,

Figure 6

Molecular representation of repressed (left), in absence of hh ligands and activated (right) KGN induced hh signalling pathway, in presence of hh ligands. Adapted from Ok CY, Singh RR, Vega F. Aberrant activation of the hedgehog signaling pathway in malignant hematological neoplasms. Am J Med. 2012;180(1):2–11. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Figure 7

Molecular mechanism of KGN induced AMPK-SIRT1/Antioxidant signalling pathway.,

Figure 8

The molecular mechanism of KGN induced JNK/RUNX-1 signalling pathway. Reproduced from Jing H, Zhang X, Gao M, et al. Kartogenin preconditioning commits mesenchymal stem cells to a precartilaginous stage with enhanced chondrogenic potential by modulating JNK and β‐catenin–related pathways. FASEB J. 2019;33(4):5641–5653. © FASEB.

Figure 9

Schematic diagram of KGN delivery system and application as biomaterials.