Smerdel-Ramoya Anna, Zanotti Stefano, Stadmeyer Lisa, Durant Deena, Canalis Ernesto
Department of Research, Saint Francis Hospital and Medical Center, 114 Woodland Street, Hartford, Connecticut 06105-1299, USA.
Endocrinology. 2008 Sep;149(9):4374-81. doi: 10.1210/en.2008-0254. Epub 2008 Jun 5.
Connective tissue growth factor (CTGF), a member of the CCN family of proteins, is expressed in skeletal cells, and the ctgf null mutation leads to neonatal lethality due to defects in skeletal development. To define the function of CTGF in the postnatal skeleton, we created transgenic mice overexpressing CTGF under the control of the human osteocalcin promoter. CTGF transgenic female and male mice exhibited a significant decrease in bone mineral density, compared with wild-type littermate controls. Bone histomorphometry revealed that CTGF overexpression caused decreased trabecular bone volume due to impaired osteoblastic activity because mineral apposition and bone formation rates were decreased. Osteoblast and osteoclast number and bone resorption were not altered. Calvarial osteoblasts and stromal cells from CTGF transgenics displayed decreased alkaline phosphatase and osteocalcin mRNA levels and reduced bone morphogenetic protein (BMP) signaling mothers against decapentaplegic, Wnt/beta-catenin, and IGF-I/Akt signaling. In conclusion, CTGF overexpression in vivo causes osteopenia, secondary to decreased bone formation, possibly by antagonizing BMP, Wnt, and IGF-I signaling and activity.
结缔组织生长因子（CTGF）是CCN蛋白家族的成员之一，在骨骼细胞中表达，ctgf基因敲除突变会因骨骼发育缺陷导致新生小鼠死亡。为了确定CTGF在出生后骨骼中的功能，我们构建了在人骨钙素启动子控制下过表达CTGF的转基因小鼠。与野生型同窝对照相比，CTGF转基因雌雄小鼠的骨矿物质密度显著降低。骨组织形态计量学显示，由于成骨细胞活性受损，CTGF过表达导致小梁骨体积减少，因为矿物质沉积和骨形成率降低。成骨细胞和破骨细胞数量以及骨吸收未发生改变。来自CTGF转基因小鼠的颅骨成骨细胞和基质细胞显示碱性磷酸酶和骨钙素mRNA水平降低，骨形态发生蛋白（BMP）信号通路、Wnt/β-连环蛋白信号通路以及IGF-I/Akt信号通路减弱。总之，体内CTGF过表达会导致骨质减少，继发于骨形成减少，可能是通过拮抗BMP、Wnt和IGF-I信号通路及活性实现的。
