Aberrant expression of Twist1 in diseased articular cartilage and a potential role in the modulation of osteoarthritis severity

Abstract

The bHLH transcription factor Twist1 has emerged as a negative regulator of chondrogenesis in skeletal progenitor cells and as an inhibitor of maturation in growth plate chondrocytes. However, its role in articular cartilage remains obscure. Here we examine Twist1 expression during re-differentiation of expanded human articular chondrocytes, the distribution of Twist1 proteins in normal versus OA human articular cartilage, and its role in modulating OA development in mice. High levels of Twist1 transcripts were detected by qPCR analyses of expanded de-differentiated human articular chondrocytes that had acquired mesenchymal-like features. The induction of hallmark cartilage genes by Bmp-2 mediated chondrogenic differentiation was paralleled by the dramatic suppression of Twist1 in vitro. In normal human articular cartilage, Twist1-expressing chondrocytes were most abundant in the superficial zone with little to no expression in the middle and deep zones. However, our analyses revealed a higher proportion of deep zone articular chondrocytes expressing Twist1 in human OA cartilage as compared to normal articular cartilage. Moreover, Twist1 expression was prominent within proliferative cell clusters near fissure sites in more severely affected OA samples. To assess the role of Twist1 in OA pathophysiology, we subjected wild type mice and transgenic mice with gain of Twist1 function in cartilage to surgical destabilization of the medial meniscus. At 12 weeks post-surgery, micro-CT and histological analyses revealed attenuation of the OA phenotype in Twist1 transgenic mice compared to wild type mice. Collectively, the data reveal a role for Twist in articular cartilage maintenance and the attenuation of cartilage degeneration.

Articular cartilage protection in Ctsk‐/‐ mice is associated with cellular and molecular changes in subchondral bone and cartilage matrix

“…We performed surgical destabilization of the medial meniscus (DMM) in 8 week old WT and Ctsk ‐/‐ mice to induce OA as previously described (Guzzo et al, ; Pelletier et al, ). Mice were anesthetized with ketamine/xylazine and DMM surgery performed on the right limb of each mouse.…”

“…Histology and histomorphometry were performed as previously described (Gentile et al, ; Guzzo et al, ; Soung, Gentile, Duong, & Drissi, ). Briefly, bones were fixed in 10% neutral buffered formalin for 7 days, decalcified in 14% EDTA (pH 7.2) for 14 days and embedded in paraffin.…”

Targeting anti‐chondrogenic factors for the stimulation of chondrogenesis: A new paradigm in cartilage repair

“…TWIST1 regulates the early stages of chondrogenesis through a competitive binding to SOX9 DNA‐binding domain, causing reduced expression of SOX9 downstream chondrocyte‐specific genes . However, in vivo work based on TWIST1 overexpression in COL2A1‐expressing cells revealed a protective effect on cartilage degeneration in OA, likely due to a functional role in the maintenance of chondro‐progenitor cells . These seemingly contrasting effects of TWIST1 highlight how the therapeutic targeting of anti‐chondrogenic factors should take into account the temporal, spatial and cell type‐specific effects in different pathophysiological conditions.…”

“…52 However, in vivo work based on TWIST1 overexpression in COL2A1-expressing cells revealed a protective effect on cartilage degeneration in OA, likely due to a functional role in the maintenance of chondro-progenitor cells. 53 These seemingly contrasting effects of TWIST1 highlight how the therapeutic targeting of anti-chondrogenic factors should take into account the temporal, spatial and cell type-specific effects in different pathophysiological conditions. Differentiated embryo chondrocyte 2 (DEC2) is another member of the helix-loop-helix family of transcription factors that was described as negative regulator of proliferation and chondrogenesis in bone marrow hMSCs.…”

Investigação funcional do novo locus candidato, HDAC9, causativo da síndrome aurículo-condilar

“…Many works have shown TWIST1 as a negative regulator of chondrogenic differentiation and one of the mechanisms proposed for the repressor activity of TWIST1 is through binding to SOX9 3'UTR, inhibiting SOX9 transactivity action. Additionally, silencing of TWIST1 causes upregulation of ACAN and Col2, chondrogenic markers (Goodnough et al, 2012;Guzzo et al, 2016;Gu et al 2012, Reinhold et al, 2006Cleary et al, 2017). Therefore, ectopic expression of TWIST1 in development may also compromise chondrogenesis, a critical process for mandible and external ear development, which are both altered in ACS individuals.…”