Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis

Abstract

Cellular senescence is a driver of various aging-associated disorders, including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (hMSCs) and ameliorating osteoarthritis in mice. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 nuclease (Cas9)-mediated knockout (KO) of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP cooperated with TEA domain transcriptional factor (TEAD) to activate the expression of forkhead box D1 (FOXD1), a geroprotective protein. YAP deficiency led to the down-regulation of FOXD1. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vector encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP–FOXD1, a novel aging-associated regulatory axis, as a potential target for gene therapy to alleviate osteoarthritis.

Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice

“…We found 737 significantly downregulated genes in the AB uninjured group compared to the VEH uninjured group. These genes included regulators of skeletal development ( Alpl [ 37 ], Col6a1 [ 54 ], Col6a2 [ 55 ], Sox9 [ 37 ], Sox11 [ 56 ], and Wnt9a [ 57 ]), Hippo signaling ( Tead1 , Tead4 [ 58 ], and Yap1 [ 59 ]), muscle contraction ( Myh8 , Myh2 , and Myom2 ), and inflammatory response ( Tlr5 [ 60 ], Ccl8 [ 61 ], Cxcl13 [ 37 ], C5ar1 [ 62 ], Cxcr1 [ 63 ], and Foxo6 [ 64 ]). Inflammatory gene comparison between AB injured and uninjured groups compared to the corresponding VEH groups are shown in Figure 5 A and Table 1 .…”

Detailed analysis of public RNAseq data and long non-coding RNA: a proposed enhancement to mesenchymal stem cell characterisation

“…In Fu et al study [96], YAP, but not TAZ, was found to safeguard MSCs from cellular senescence as shown by KO experiments. Interestingly, YAP KO, but not TAZ, significantly increases the expression of Mlinc.28428.2.…”

Inhibition of microRNA‐27b‐3p relieves osteoarthritis pain via regulation of KDM4B‐dependent DLX5

“…11 The pathogenesis of OA has been linked with the senescence of BMSCs while osteogenesis differentiation has been associated with the delay of the aging process, whereas adipogenic differentiation results in accelerated MSC aging process. 6,7 A recent study revealed that miR-27a-3p could promote the osteogenic differentiation of MSCs by targeting ATF3, thereby relieving OA symptoms. 31 In a word, miR-27b-3p may be a potentially promising regulator in the osteogenesis differentiation and adipogenic differentiation of BMSCs and also a vital mediator of OA.…”

“…5 The pathogenesis of OA has been speculated to be associated with the senescence of mesenchymal stem cells (MSCs). 6,7 A cell therapy method based on MSCs has been validated to be a promising OA treatment approach. 8 Accumulating data have indicated the significance of microRNAs (miRNAs) in the regulatory mechanisms associated with various inflammation-mediated diseases.…”