The combination of microfracture with induction of Wnt / β- Catenin pathway, leads to enhanced cartilage regeneration

Abstract

IntroductionMicrofracture does not lead to complete healing of full-thickness cartilage defects. The aim of this study was to evaluate the effect of modifying Wnt/β-catenin signaling following microfracture, on the restoration of a full-thickness cartilage defect in a rabbit model. The modification of the canonical Wnt pathway was achieved through per os administration of lithium carbonate, which is an intracellular inhibitor of glycogen synthase kinase 3-β (Gsk3-β) and therefore induces Wnt/β-catenin signaling.Materials and methodsFull-thickness cartilage defects of 4 mm in diameter were created in the patellar groove of the right femurs of 18 male New Zealand white rabbits. The rabbits were divided into three groups of six (n = 6) based on post-surgery treatment differences, as follows: microfracture only (group 1), microfracture plus lithium carbonate 7 mM in the drinking water for 1 week (group 2), microfracture plus lithium carbonate 7 mM in the drinking water for 4 weeks (group 3). All animals were sacrificed 9 weeks after surgery. The outcome was assessed histologically, by using the International Cartilage Repair Society (ICRS) visual histological scale. Immunohistochemistry for type II collagen was also conducted.ResultsStatistical analysis of the histological ICRS scores showed that group 3 was significantly superior to group 1 in four out of six ICRS categories, while group 2 was superior to 1 in only two out of six.ConclusionThe combination of microfracture and systematic administration of lithium carbonate 7 mM for 4 weeks shows statistically significant superiority in four out of six ICRS categories compared with microfracture only for the treatment of full-thickness cartilage defects in a rabbit experimental model.

Inhibition versus activation of canonical Wnt-signaling, to promote chondrogenic differentiation of Mesenchymal Stem Cells. A review.

“…These serum levels are slightly lower than the range of 0.6-1.2 mM/L, concentrations achieved and maintained during lithium therapy in human subjects. 26 This ostensibly low serum concentration was enough to induce chondrogenic differentiation of the bone marrow-derived MSCs accumulated inside the microfracture clot. In the case of extracellular Wnt inhibitors, a dose-dependent effect is also observed, as the higher dose of DKK1 resulted in a 30% reduction of the pre-hypertrophic population, whereas the lower amount reduced the pre-hypertrophic population by 46%.…”

“…The 1-week treatment group was superior to the control group in two out of six ICRS categories. 26 The aforementioned studies are summarized in Table 1.…”

“…These findings are also supported by data from our animal model, as induction of Wnt signaling during only the first-week post microfracture was not sufficient to exert the beneficial effect of the 4-week treatment upon the histological properties of the repair tissue. 26 Potential limitations of utilizing Wnt signaling activation in clinical practice originate from the consideration that this process could increase the possibility of susceptibility to carcinogenesis. Constitutive Wnt activation by genetic mutation of intracellular signaling components such as β-catenin has been shown to cause tumors in several tissues, including the liver and colon.…”

The Beneficial Effect of an Intra-articular Injection of Losartan on Microfracture-Mediated Cartilage Repair Is Dose Dependent

“…12 These techniques include combining cells, scaffolds and growth factors, or chemical drug therapies with marrow stimulation techniques to enhance the quality of repaired cartilage. 7,14,29,37,41,45,47 Angiotensin receptors are expressed in hypertrophic cartilage and are implicated in osteoarthritis (OA) development. 58 Furthermore, it also has been shown that the angiotensin II–induced activation of transforming growth factor β1 (TGF-β1)–phosphorylated small mothers against decapentaplegic 2/3 (pSmad2/3) signaling is associated with tissue fibrosis.…”

Network‐Based Pharmacology and Bioinformatics Study on the Mechanism of Action of Gujiansan in the Treatment of Steroid‐Induced Avascular Necrosis of the Femoral Head

“…In the osteoblast experiments in this study, the results of qRT-PCR indicated that quercetin could significantly promote the upregulation of IL-1β gene expression in SANFH osteoblasts; studies also showed that IL-1β could inhibit the production of DKK1, thereby promoting the activation of Wnt signaling [59]. The activation of Wnt signaling could enhance the formation of MSC cartilage [60][61][62]. Therefore, it suggests that quercetin in this study may activate the Wnt signaling pathway by upregulating IL-1β gene expression in osteoblasts and finally promote cartilage formation.…”