Induction of Krüppel‐like factor 2 reduces K/BxN serum‐induced arthritis

Abstract

Krüppel‐like factor 2 (KLF2) critically regulates activation and function of monocyte, which plays important pathogenic role in progressive joint destruction in rheumatoid arthritis (RA). It is yet to be established the molecular basis of KLF2‐mediated regulation of monocytes in RA pathogenesis. Herein, we show that a class of compound, HDAC inhibitors (HDACi) induced KLF2 expression in monocytes both in vitro and in vivo. KLF2 level was also elevated in tissues, such as bone marrow, spleen and thymus in mice after infusion of HDACi. Importantly, HDACi significantly reduced osteoclastic differentiation of monocytes with the up‐regulation of KLF2 and concomitant down‐regulation of matrixmetalloproteinases both in the expression level as well as in the protein level. In addition, HDACi reduced K/BxN serum‐induced arthritic inflammation and joint destruction in mice in a dose‐dependent manner. Finally, co‐immunoprecipitation and overexpression studies confirmed that KLF2 directly interacts with HDAC4 molecule in cells. These findings provide mechanistic evidence of KLF2‐mediated regulation of K/BxN serum‐induced arthritic inflammation.

Transcriptional Regulation of Osteoclastogenesis: The Emerging Role of KLF2

“…Specifically in mice, induction of KLF2 in immune cells reduced arthritic inflammation and attenuated joint destruction. Furthermore, coimmunoprecipitation confirmed the direct interaction between KLF2 and HDAC4, thereby providing the groundwork to understand the molecular mechanisms whereby KLF2 regulates RA pathogenesis (80). Altogether, these data demonstrate a novel protective role of KLF2 in regulation of RA severity and progression.…”

“…Together, the data indicate that KLF2 plays an important role in attenuating inflammation and inhibiting osteoclastogenic differentiation and function in RA. ; data from our lab show that KLF2 knockdown significantly increased enrichment of the active histone marks H3K9Ac and H4K8Ac and respective histone acetylase transfer (HAT) enzymes P300 and PCAF at the enrichment sites for the MMP9 gene (80). KLF2 inhibits pro-inflammatory markers, thereby further inhibiting monocytic activation (72).…”

“…While KLF2 has a demonstrable role in osteoclastogenesis, the mechanisms governing this interaction are not well-understood (Figure 4). Recent reports detail work done in a K/BxN seruminduced model of rheumatoid arthritis which further illumines the role of KLF2 in regulating disease progression (80). In this study, RA induction was more pronounced in KLF2 hemizygous (KLF2 +/− ) mice compared to wild type (WT) animals; more ankle swelling and more severe immunohistochemical signs of inflammation and tissue damage were detected in the KLF2 +/− mice, whereas WT animals showed only mild signs of arthritic pathogenesis.…”

KLF2 regulates dental pulp-derived stem cell differentiation through the induction of mitophagy and altering mitochondrial metabolism

“…KLF2 is one of the important members of the KLF family, which was first identified as a critical regulator for normal lung development [ 27 ]. Later it was revealed that it has implications in many important biological processes, such as T cell migration [ 28 ], embryonic erythropoiesis [ 29 ], vascular integrity [ 30 ], and monocyte activation, function, and differentiation [ 11 , [31] , [32] , [33] , [34] ]. Studies suggest that KLF2 is essential for maintaining ground state pluripotency of mouse embryonic stem cells [ 35 ], differentiation of endothelial progenitor cells to endothelial cells induced by shear stress [ 36 ].…”

Myeloid Krüppel-Like Factor 2 Critically Regulates K/BxN Serum-Induced Arthritis

“…The transcription factor Krüppel-like factor 2 (KLF2) plays an important role in the regulation of a variety of immune cells, including proinflammatory activation and function of monocytes [18,19,20,21], and myeloid cell polarization [22]. KLF2, also known as lung KLF, as it was first found in the adult mouse lung [23], plays a major regulatory role in hematopoietic cell biology, including cell quiescence, cell proliferation, differentiation, and survival [24].…”