CITED2 mediates the mechanical loading–induced suppression of adipokines in the infrapatellar fat pad

Abstract

Adipokines secreted from the infrapatellar fat pad (IPFP), such as adipsin and adiponectin, have been implicated in osteoarthritis pathogenesis. CITED2, a mechanosensitive transcriptional regulator with chondroprotective activity, may modulate their expression. Cited2 haploinsufficient mice (Cited2+/−) on a high‐fat diet (HFD) exhibited increased body weight and increased IPFP area compared to wild‐type (WT) mice on an HFD. While an exercise regimen of moderate treadmill running induced the expression of CITED2, as well as PGC‐1α, and reduced the expression of adipsin and adiponectin in the IPFP of WT mice on an HFD, Cited2 haploinsufficiency abolished the loading‐induced expression of PGC‐1α and loading‐induced suppression of adipsin and adiponectin. Furthermore, knocking down or knocking out CITED2 in adipose stem cells (ASCs)/preadipocytes derived from the IPFP in vitro led to the increased expression of adipsin and adiponectin and reduced PGC‐1α, and abolished the loading‐induced suppression of adipsin and adiponectin and loading‐induced expression of PGC‐1α. Overexpression of PGC‐1α in these ASC/preadipocytes reversed the effects caused by CITED2 deficiency. The current data suggest that CITED2 is a critical regulator in physiologic loading‐induced chondroprotection in the context of an HFD and PGC‐1α is required for the inhibitory effects of CITED2 on the expression of adipokines such as adipsin and adiponectin in the IPFP.

PGC-1α in osteoarthritic chondrocytes: From mechanism to target of action

“…Activation of PGC-1α by PPAR-γ promotes Liver X receptors (LXR) expression, reduces cholesterol deposition on the joint surface, and maintains normal joint function and bone development ( Ratneswaran et al, 2017 ). PGC-1α, which can be activated by Glu/Asp rich carboxy-terminal domain 2 (CITED2), plays a critical role in regulating load-induced adiponectin and inhibiting adiponectin expression in human infrapatellar fat pad-derived adipose stem cells/preadipocytes ( Liu et al, 2019 ). In conclusion, PGC-1α is associated with obesity-induced OA and is involved in the regulation of abnormal glucose metabolism and lipid metabolism in OA chondrocytes ( Ryu et al, 2020 ) ( Figure 2 ).…”

CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation

“…CITED2 (CBP/p300-interacting-transactivator-with-an ED-rich-tail 2) is a transcriptional regulator that co-activates or represses multiple transcription factors, including AP-2 ( Bamforth et al., 2001 ), HIF-1alpha ( Bhattacharya et al., 1999 ), PPAR-α ( Tien et al., 2004 ), SMAD2/3 ( Chou and Yang, 2006 ), and c-MYC ( Chou et al., 2012 ) to regulate fundamental cellular processes, such as proliferation, metabolism, differentiation, migration, and autophagy. Consistent with its ubiquitous expression and pleiotropic impact on diverse transcription factors, CITED2 is essential for embryonic development, including fetal liver hematopoiesis ( Bamforth et al., 2001 , 2004 ; Chen et al., 2007 ; Weninger et al., 2005 ; Withington et al., 2006 ; Yin et al., 2002 ), ESC biology ( Kranc et al., 2015 ; Li et al., 2012 ), adult tissue functions ( Kim et al., 2018 ; Lee et al., 2009 ; Liu et al., 2019 ), cellular proliferation ( Kranc et al., 2003 ), and cancer progression ( Fernandes et al., 2020 ). Thus, CITED2 is an important regulator of diverse molecular, cellular, and developmental processes.…”