Download Statin treatment rescues FGFR3 skeletal dysplasia phenotypes

Statin treatment rescues FGFR3 skeletal dysplasia phenotypes
Akihiro Yamashita,1, Miho Morioka,1, Hiromi Kishi,1, Takeshi Kimura,1, 2, Yasuhito Yahara,1, Minoru Okada,1, Kaori Fujita,1,
Hideaki Sawai,3, Shiro Ikegawa4, & Noriyuki Tsumaki1, 5,
Nature 513, 507-511(2014)
報告學生：劉政德
指導老師：彭致文
評講學生: 詹昊學長與楊勤皓學長
演講日期：2014/10/21
Abstract：
ACHONDROPLASIA, the most common cause of chondrodysplasia and skeletal dysplasia,
is a condition of unknown origin characterized by short-limbed dwarfism. The patient who
suffered
from
the
disease
expressed
a
mutant
form
of
gene
that
encodes
fibroblast-growth-factor receptor 3(FGFR3) (on chromosome 4p l6.3) within articular
chondrocytes. Activating six mutations in FGFR3 tyrosine kinase cause several forms of
human skeletal dysplasia, there are four ways to identify different patients by molecular
analysis: Hypochondrodysplasia, achondrodysplasia, thanatophoric dysplasia type I (TD1)
and II (TD2). Previously, several studies have demonstrated that ERK and p38 MAP kinases
but not STAT1 are important to FGFR3-mediated growth inhibition of chondrocytes both in
vitro and in vivo. However, FGFR3 mutants associated with skeletal overgrowth, promote
apoptosis and cartilage abnormalities on engineered mouse models in vivo. In this paper, a
new idea of cell reprogramming technologies was used to establish a disease model---by
induced pluripotent stem cell (iPSC). Firstly, the iPSCs are generated from the dermal
fibroblast
of
TD1
patients,
and
was
differentiated
into
chondrocytes
with
FGFR3-mutation-mediated chondrodysplasia phenotypes. The author also checked the
chondrogenic differentiation in wild-type and TD1 iPSCs by checking genetic markers
through real-time–PCR. To identified the difference between the wild-type iPSCs and TD1
iPSC by histology assay and the chondrogenic of FGFR3 mRNA and protein levels.
Interestingly, comparing the expression level of FGFR3 mRNA in wild-type and TD1 iPSCs,
they found that the amount of mRNA was higher in wild-type, but in protein expression level
was
diminished.
Indeed,
by
reducing
the
amount
of
FGFR
can
rescue
TD1-iPSCs-differentited chondrocytes through shFGFR3 system. Finally, they showed that
statins can promote the degradation of the FGFR3 mutants in chondrogenically differentiated
TD1 iPSC. The author provides a human ACH model to study the onset and progression of
disease, and expects to establish a platform for drug screening.
Reference
1. Krejci, P. et al. Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant
role of STAT1 in FGFR3 signaling in cartilage. PLoS ONE 3, e3961 (2008).
2. Legeai-Mallet, L.,Benoist-Lasselin, C., Delezoide, A. L.,Munnich, A.&Bonaventure, J. Fibroblast growth factor receptor 3
mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia. J. Biol. Chem. 273,
13007–13014 (1998).