Multifaceted signaling regulators of chondrogenesis: Implications in cartilage regeneration and tissue engineering (original) (raw)
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International Orthopaedics, 2014
Purpose The use of stem cells in regenerative medicine offers hope to treat numerous orthopaedic disorders, including articular cartilage defects. Although much research has been carried out on chondrogenesis, this complicated process is still not well understood and much more research is needed. The present review provides an overview of the stages of chondrogenesis and describes the effects of various growth factors, which act during the multiple steps involved in stem celldirected differentiation towards chondrocytes. Methods The current literature on stem cell-directed chondrogenesis, in particular the role of members of the transforming growth factor-β (TGF-β) superfamily-TGF-βs, bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs)-is reviewed and discussed. Results Numerous studies have reported the chondrogenic potential of both adult-and embryonic-like stem cells and the role of growth factors in programming differentiation of these cells towards chondrocytes. Mesenchymal stem cells (MSCs) are adult multipotent stem cells, whereas induced pluripotent stem cells (iPSC) are reprogrammed pluripotent cells. Although better understanding of the processes involved in the development of cartilage tissues is necessary, both cell types may be of value in the clinical treatment of cartilage injuries or osteoarthritic cartilage lesions. Conclusions MSCs and iPSCs both present unique characteristics. However, at present, it is still unclear which cell type is most suitable in the treatment of cartilage injuries.
Journal of Tissue Engineering and Regenerative Medicine, 2013
Articular cartilage is easily damaged, yet difficult to repair. Cartilage tissue engineering seems a promising therapeutic solution to restore articular cartilage structure and function, with mesenchymal stem cells (MSCs) receiving increasing attention for their promise to promote cartilage repair. It is known from embryology that members of the fibroblast growth factor (FGF), transforming growth factor-b (TGFb) and wingless-type (Wnt) protein families are involved in controlling different differentiation stages during chondrogenesis. Individually, these pathways have been extensively studied but so far attempts to recapitulate embryonic development in in vitro MSC chondrogenesis have failed to produce stable and functioning articular cartilage; instead, transient hypertrophic cartilage is obtained. We believe a better understanding of the simultaneous integration of these factors will improve how we relate embryonic chondrogenesis to in vitro MSC chondrogenesis. This narrative review attempts to define current knowledge on the crosstalk between the FGF, TGFb and Wnt signalling pathways during different stages of mesenchymal chondrogenesis. Connecting embryogenesis and in vitro differentiation of human MSCs might provide insights into how to improve and progress cartilage tissue engineering for the future.
Tissue Engineering Part B: Reviews, 2009
Cartilage is the first skeletal tissue to be formed during embryogenesis leading to the creation of all mature cartilages and bones, with the exception of the flat bones in the skull. Therefore, errors occurring during the process of chondrogenesis, the formation of cartilage, often lead to severe skeletal malformations such as dysplasias. There are hundreds of skeletal dysplasias, and the molecular genetic etiology of some remains more elusive than of others. Many efforts have aimed at understanding the morphogenetic event of chondrogenesis in normal individuals, of which the main morphogenetic and regulatory mechanisms will be reviewed here. For instance, many signaling molecules that guide chondrogenesis-for example, transforming growth factor-b, bone morphogenetic proteins, fibroblast growth factors, and Wnts, as well as transcriptional regulators such as the Sox family-have already been identified. Moreover, extracellular matrix components also play an important role in this developmental event, as evidenced by the promotion of the chondrogenic potential of chondroprogenitor cells caused by collagen II and proteoglycans like versican. The growing evidence of the elements that control chondrogenesis and the increasing number of different sources of progenitor cells will, hopefully, help to create tissue engineering platforms that could overcome many developmental or degenerative diseases associated with cartilage defects.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2015
a b s t r a c t 1 8 growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but 32 the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/ 33 β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. 34 Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated 35 suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to 36 inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. 37 Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular 38 matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the 39 FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of 40 matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating 41 RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling 42 rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF 43 signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation. 44 © 2015 Published by Elsevier B.V. 45 46 47 48 49 1. Introduction 50 Endochondral ossification, in which bone replaces pre-existing 51 cartilage, is the predominant mechanism of longitudinal bone growth. 52 Bones grow longer at the epiphyseal growth plates, where chondrocytes 53 progress through a series of differentiation stages. Chondrocytes leave 54 their resting state, proliferate in columns, exit the cell cycle and undergo 55 hypertrophy, during which they mineralize their matrix and undergo 56 apoptosis. The cartilage is then replaced by bone [1]. FGF signaling 57 represents one of the major regulators of this process. Removal of 58 FGF-receptor 3 (FGFR3) leads to skeletal overgrowth in mice [2], where-59 as activating mutations in FGFR3 account for several skeletal dysplasias 60 in humans, e.g., achondroplasia (ACH), which is the most prevalent 61 short-limbed dwarfism, and thanatophoric dysplasia (TD), which repre-62 sents the most common lethal skeletal dysplasia [3]. 63 One of the hallmark features of FGFR3-related skeletal dysplasia is 64 profound disruption of the growth plate architecture, which, in TD, 65 leads to small or non-existing columns of hypertrophic chondrocytes 66 [4]. This demonstrates the negative effect of aberrant FGF signaling on 67 chondrocyte differentiation, although the mechanisms underlying this 68 phenotype remain unclear. One explanation for this may be FGFR3 in-69 terference with indian hedgehog (Ihh)/parathyroid hormone-related Biochimica et Biophysica Acta xxx (2015) xxx-xxx ⁎ j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b b a d i s Please cite this article as: M. Buchtova, et al., Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experim..., Biochim. Biophys. Acta (2015), http://dx.
Stem Cells and Development, 2012
Adult mesenchymal stem cells (MSCs) are an attractive cell source for cartilage tissue engineering. In vitro predifferentiation of MSCs has been explored as a means to enhance MSC-based articular cartilage repair. However, there remain challenges to control and prevent the premature progression of MSC-derived chondrocytes to the hypertrophy. This study investigated the temporal effect of transforming growth factor (TGF)-b and b-catenin signaling co-activation during MSC chondrogenic differentiation and evaluated the influence of these predifferentiation conditions to subsequent phenotypic development of the cartilage. MSCs were differentiated in chondrogenic medium that contained either TGFb alone, TGFb with transient b-catenin coactivation, or TGFb with continuous b-catenin coactivation. After in vitro differentiation, the pellets were transplanted into SCID mice. Both coactivation protocols resulted in the enhancement of chondrogenic differentiation of MSCs. Compared with TGFb activation, transient coactivation of TGFb-induction with b-catenin activation resulted in heightened hypertrophy and formed highly ossified tissues with marrow-like hematopoietic tissue in vivo. The continuous coactivation of the 2 signaling pathways, however, resulted in inhibition of progression to hypertrophy, marked by the suppression of type X collagen, Runx2, and alkaline phosphatase expression, and did not result in ossified tissue in vivo. Chondrocytes of the continuous co-activation samples secreted significantly more parathyroid hormone-related protein (PTHrP) and expressed cyclin D1. Our results suggest that temporal coactivation of the TGFb signaling pathway with b-catenin can yield cartilage of different phenotype, represents a potential MSC predifferentiation protocol before clinical implantation, and has potential applications for the engineering of cartilage tissue.
PLOS ONE, 2015
Cartilage is a tissue with limited self-healing potential. Hence, cartilage defects require surgical attention to prevent or postpone the development of osteoarthritis. For cell-based cartilage repair strategies, in particular autologous chondrocyte implantation, articular chondrocytes are isolated from cartilage and expanded in vitro to increase the number of cells required for therapy. During expansion, the cells lose the competence to autonomously form a cartilage-like tissue, that is in the absence of exogenously added chondrogenic growth factors, such as TGF-βs. We hypothesized that signaling elicited by autocrine and/ or paracrine TGF-β is essential for the formation of cartilage-like tissue and that alterations within the TGF-β signaling pathway during expansion interfere with this process. Primary bovine articular chondrocytes were harvested and expanded in monolayer culture up to passage six and the formation of cartilage tissue was investigated in high density pellet cultures grown for three weeks. Chondrocytes expanded for up to three passages maintained the potential for autonomous cartilage-like tissue formation. After three passages, however, exogenous TGF-β1 was required to induce the formation of cartilage-like tissue. When TGF-β signaling was blocked by inhibiting the TGF-β receptor 1 kinase, the autonomous formation of cartilage-like tissue was abrogated. At the initiation of pellet culture, chondrocytes from passage three and later showed levels of transcripts coding for TGF-β receptors 1 and 2 and TGF-β2 to be three-, five-and five-fold decreased, respectively, as compared to primary chondrocytes. In conclusion, the autonomous formation of cartilage-like tissue by expanded chondrocytes is dependent on signaling induced by autocrine and/or paracrine TGF-β. We propose that a decrease in the expression of the chondrogenic growth factor TGF-β2 and of the TGF-β receptors in expanded chondrocytes accounts for a decrease in the activity of the TGF-β signaling pathway and hence for the loss of the potential for autonomous cartilage-like tissue formation.
Chondrogenesis, joint formation, and articular cartilage regeneration
Journal of Cellular Biochemistry, 2009
The repair of joint surface defects remains a clinical challenge, as articular cartilage has a limited healing response. Despite this, articular cartilage does have the capacity to grow and remodel extensively during pre-and post-natal development. As such, the elucidation of developmental mechanisms, particularly those in post-natal animals, may shed valuable light on processes that could be harnessed to develop novel approaches for articular cartilage tissue engineering and/or regeneration to treat injuries or degeneration in adult joints. Much has been learned through mouse genetics regarding the embryonic development of joints. This knowledge, as well as the less extensive available information regarding post-natal joint development is reviewed here and discussed in relation to their possible relevance to future directions in cartilage tissue repair and regeneration.
Journal of Tissue Engineering and Regenerative Medicine, 2009
Modern tissue engineering concepts integrate cells, scaffolds, signalling molecules and growth factors. For the purposes of regenerative medicine, fetal development is of great interest because it is widely accepted that regeneration recapitulates in part developmental processes. In tissue engineering of cartilage the growth plate of the long bone represents an interesting, well-organized developmental structure with a spatial distribution of chondrocytes in different proliferation and differentiation stages, embedded in a scaffold of extracellular matrix components. The proliferation and differentiation of these chondrocytes is regulated by various hormonal and paracrine factors. Thus, members of the TGFβ superfamily, the parathyroid hormone-related peptide-Indian hedgehog loop and a number of transcription factors, such as Sox and Runx, are involved in the regulation of chondrocyte proliferation and differentiation. Furthermore, adhesion molecules, homeobox genes, metalloproteinases and prostaglandins play a role in the complex regulation mechanisms. The present paper summarizes the morphological organization of the growth plate and provides a short but not exhaustive overview of the regulation of growth plate development, giving interesting insights for tissue engineering of cartilage.
Current Rheumatology Reviews, 2008
Studies of chondrogenesis and embryonic limb development offer a wealth of knowledge regarding signals that regulate the behavior of chondrocytes. Many such chondrogenic regulators are upregulated in osteoarthritis-affected chondrocytes, suggesting a role in pathogenesis. Yet, some of the same factors also support adult articular cartilage homeostasis, and enhance neo-cartilage tissue formation in experimental models. In this review, we summarize many of the important regulatory mechanisms involved in chondrogenesis and examine how their disruption may contribute to functional changes in articular cartilage during osteoarthritis or aging.
Expert opinion on biological therapy, 2015
Currently, joint arthroplasty remains the only definitive management of osteoarthritis, while other treatment modalities only provide temporary and symptomatic relief. The use of genetically engineered chondrocytes is currently undergoing clinical trials. Specifically, it has been designed to induce cartilage growth and differentiation in patients with degenerative arthritis, with the aim to play a curative role in the disease process. This treatment involves the incorporation of TGF-β1, which has been determined to play an influential role in chondrogenesis and extracellular matrix synthesis. Using genetic manipulation and viral transduction, TGF-β1 is incorporated into human chondrocytes and administered in a minimally invasive fashion directly to the affected joint. Following a database literature search, we evaluated the current evidence on this product and its outcomes. Furthermore, we also briefly reviewed other treatments developed for chondrogenesis and cartilage regeneratio...