Connective tissue growth factor is required for skeletal development and postnatal skeletal homeostasis in male mice.
Connective tissue growth factor (CTGF), a member of the cysteine-rich 61 (Cyr 61), CTGF, nephroblastoma overexpressed (NOV) (CCN) family of proteins, is synthesized by osteoblasts, and its overexpression inhibits osteoblastogenesis and causes osteopenia. The global inactivation of Ctgf leads to defective endochondral bone formation and perinatal lethality; therefore, the consequences of Ctgf inactivation on the postnatal skeleton are not known. To study the function of CTGF, we generated Ctgf(+/LacZ) heterozygous null mice and tissue-specific null Ctgf mice by mating Ctgf conditional mice, where Ctgf is flanked by lox sequences with mice expressing the Cre recombinase under the control of the paired-related homeobox gene 1 (Prx1) enhancer (Prx1-Cre) or the osteocalcin promoter (Oc-Cre). Ctgf(+/LacZ) heterozygous mice exhibited transient osteopenia at 1 month of age secondary to decreased trabecular number. A similar osteopenic phenotype was observed in 1-month-old Ctgf conditional null male mice generated with Prx1-Cre, suggesting that the decreased trabecular number was secondary to impaired endochondral bone formation. In contrast, when the conditional deletion of Ctgf was achieved by Oc-Cre, an osteopenic phenotype was observed only in 6-month-old male mice. Osteoblast and osteoclast number, bone formation, and eroded surface were not affected in Ctgf heterozygous or conditional null mice. In conclusion, CTGF is necessary for normal skeletal development but to a lesser extent for postnatal skeletal homeostasis.
Canalis
Ernesto
E
Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105-1299, USA. ecanalis@stfranciscare.org
Zanotti
Stefano
S
Beamer
Wesley G
WG
Economides
Aris N
AN
Smerdel-Ramoya
Anna
A
D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology; D005260:Female; D048788:Growth and Development / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology; D015675:Osteocalcin / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics*; D012727:Sex Characteristics
D018398:Homeodomain Proteins; C489936:Prrx1 protein, mouse; D015675:Osteocalcin; D055513:Connective Tissue Growth Factor