Saturday, April 4, 2009


Krüppel-like factor 4 regulates membranous and endochondral ossification.

"Klf4 is expressed in the developing flat bones but its expression diminishes postnatally. In the developing long bones, Klf4 is expressed in the perichondrium, trabecular osteoblasts and prehypertrophic chondrocytes. In contrast, osteoblasts lining at the surface of the bone collar showed extremely low levels of Klf4 expression. To investigate the possible roles played by Klf4 during skeletal development, we generated transgenic mice expressing Klf4 under mouse type I collagen regulatory sequence. Transgenic mice exhibited severe skeletal deformities and died soon after birth. Transgenic mice showed delayed formation of the calvarial bones; and over-expressing Klf4 in primary mouse calvarial osteoblasts in culture resulted in strong repression of mineralization indicating that this regulation of Klf4 is through an osteoblast-autonomous effect. Surprisingly, long bones of the transgenic mice exhibited delayed marrow cavity formation. Even at E18.5, the presumptive marrow space was occupied by cartilage anlage and invasion of the vascular endothelial cells and osteoclasts were seldom observed. Instead of entering the cartilage anlage, osteoclasts accumulated at the periosteum in the transgenic mice. Significantly, osteocalcin, which is known to chemotact osteoclasts, was up-regulated at the perichindrium as early as E14.5 in the mutants. In vitro studies showed that this induction of osteocalcin by Klf4 was regulated at its transcriptional level. Klf4 regulates normal skeletal development through coordinating the differentiation and migration of osteoblasts, chondrocytes, vascular endothelial cells and osteoclasts."

"Klf4 tends to localize in post-mitotic cells"

"in the long bones, Klf4 is expressed in the osteoprogenitor cells of the perichondrium but not in the periosteum or endosteum at the outer and inner surface of the bone collar."

"The total bone length and mineralized length ratio were both significantly reduced in the mutants at postnatal day 0"

Klf4 overexpression increased Osteocalcin{up} and MGP levels but decreased Osterix levels.  MGP inhibits cartilage mineralization.

"initial chondrogenesis and differentiation was relatively normal in the mutants. However, the formation of the POC is severely delayed in the mutants. The cells within this region did not express Col2a1 and Col10a1, expressed Col1a1 only in a narrow domain, but expressed Osp indicating that the cells were retained at late hypertrophic stage."

Klf4 overexpression decreased MMP9 and MMP13 expression.

Klf4 underexpression has negative effects too so Klf4 is likely one of those genes were optimal expression is optimal for height growth.

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