Kruppel-like Factors in Skeletal Physiology and Pathologies

Abstract

Kruppel-like factors (KLFs) belong to a large group of zinc finger-containing transcription factors with amino acid sequences resembling the Drosophila gap gene Krüppel. Since the first report of molecular cloning of the KLF family gene, the number of KLFs has increased rapidly. Currently, 17 murine and human KLFs are known to play crucial roles in the regulation of transcription, cell proliferation, cellular differentiation, stem cell maintenance, and tissue and organ pathogenesis. Recent evidence has shown that many KLF family molecules affect skeletal cells and regulate their differentiation and function. This review summarizes the current understanding of the unique roles of each KLF in skeletal cells during normal development and skeletal pathologies.

Keywords: Kruppel-like factor; osteoarthritis; osteoblast; osteoclast; osteoporosis; osteosarcoma.

Figure 2

Physical and functional association partner molecules of KLF proteins intimately involved in differentiation of skeletal cells. KLF3 [49,50,51], KLF4 [55,56,61,62,63,64], KLF5 [73,74,75,76,77], and KLF10 [110,111] interacting proteins are shown in the right box of each molecule.

Figure 1

Structural and amino acid sequence properties of KLF proteins. (A) Structure of human SP1, Drosophila melanogaster (Fly) Krüppel, and human KLF proteins. TAD: transcriptional activation domain, RD: repression domain. The green region in SP1 protein defines the Buttonhead box motif, and red region defines the zinc finger motif. Most of the KLF proteins contain three zinc finger motifs close at the carboxyl-terminal edge, while KLF9, KLF13, KLF14, and KLF16 contain zinc finger motifs more positionally shifted to the middle part of the protein indicated by the double arrow. (B) Multiple sequence alignment of three zinc fingers and preceding amino-terminal amino acid residues of Drosophila melanogaster (Fly) Buttonhead, Krüppel, human SP1/KLF family proteins. The first three zinc finger sequences are shown for the Fly Krüppel protein. Alignment was generated by MAFFT, ClustalW, and visual inspection. Buttonhead box motifs (Btd motif) are highlighted by green color. Cystein and Histidine residues of the zinc finger motifs are highlighted by yellow and blue color, respectively.