TGFβi is involved in the chondrogenic differentiation of mesenchymal stem cells and is dysregulated in osteoarthritis

Abstract

Objective: Transforming growth factor-b (TGFb) is a major regulator of cartilage homeostasis and its deregulation has been associated with osteoarthritis (OA). Deregulation of the TGFb pathway in mesenchymal stem cells (MSCs) has been proposed to be at the onset of OA. Using a secretome analysis, we identified a member of the TGFb family, TGFb-induced protein (TGFbi or bIGH3), expressed in MSCs and we investigated its function and regulation during OA. Design: Cartilage, bone, synovium, infrapatellar fat pad and bone marrow-MSCs were isolated from patients with OA or healthy subjects. Chondrogenesis of BM-MSCs was induced by TGFb3 in micropellet culture. Expression of TGFbi was quantified by RT-qPCR, ELISA or immunohistochemistry. Role of TGFbi was investigated in gain and loss of function experiments in BM-MSCs and chondrocytes. Results: TGFbi was up-regulated in early stages of chondrogenesis and its knock-down in BM-MSCs resulted in the down-regulation of mature and hypertrophic chondrocyte markers. It likely occurred through the modulation of adhesion molecules including integrin (ITG)b1, ITGb5 and N-cadherin. We also showed that TGFbi was upregulated in vitro in a model of OA chondrocytes, and its silencing enhanced the hypertrophic marker type X collagen. In addition, TGFbi was up-regulated in bone and cartilage from OA patients while its expression was reduced in BM-MSCs. Similar findings were observed in a murine model of OA. Conclusions: Our results revealed a dual role of TGFbi during chondrogenesis and pointed its deregulation in OA joint tissues. Modulating TGFbi in BM-MSCs might be of interest in cartilage regenerative medicine.

TGFBI secreted by mesenchymal stromal cells ameliorates osteoarthritis and is detected in extracellular vesicles

“…In 3-day-old mice, cartilage is predominantly pre-hypertrophic and hypertrophic, consistent with high TGFBI expression, as observed during embryogenesis. We previously reported that TGFBI is required at the early stages of chondrogenic differentiation of MSCs, and is then downregulated in mineralized hypertrophic chondrocytes [21]. The present study brings evidence that besides promoting endochondral ossification and inhibiting mineralization during in vitro differentiation of mature osteoblasts or chondrocytes, TGFBI deregulation in joint tissues might contribute to OA.…”

“…Importantly, the higher chondroprotective effect in OA mice of FRA-1-overexpressing adipose-derived stromal cells compared with wild type cells has been associated with increased POSTN expression [42]. We recently reported TGFBI upregulation in bone and cartilage from patients and mice with OA [21]. Based on the similarity of functions and expression in OA, all these data suggest a possible common regulation of POSTN and TGFBI in OA and identify these two molecules as important players in joint homeostasis.…”

“…TGFBI is deregulated in OA-like femoral head explants and chondrocytes. We previously showed by immunohistochemistry that TGFBI is upregulated in the cartilage from patients with OA and in CIOA mice compared with healthy controls [28]. To better understand the effect of TGFBI deregulation, we first evaluated its expression by RT-qPCR in mice at different ages.…”

“…Interestingly, deregulation of TGFβ signalling in MSCs is involved in OA onset or progression, and knock out of TGFβ type II receptor in MSCs attenuates cartilage erosion and subchondral bone sclerosis [20]. We recently reported that TGFβ-induced gene product-h3 (TGFBI/BIGH3/RGD-CAP) is upregulated in cartilage and bone from patients with OA, whereas it is downregulated in bone marrow-derived human MSCs (hMSCs) [21]. We also found that TGFBI downregulation in hMSCs partly compromises their chondrogenic potential.…”

Recent Advance in Source, Property, Differentiation, and Applications of Infrapatellar Fat Pad Adipose-Derived Stem Cells

“…Osteoarthritis can affect the chondrogenic differentiation potential of IPFP-ASCs [32]. The decreased chondrogenic differentiation potential of IPFP-ASCs may be associated with the downregulation of TGF-β gene expression in osteoarthritis [33]. It remains to be further investigated whether the IPFP-ASCs with stronger chondrogenic differentiation potential can be obtained by gene knockout.…”