Disruption of four-and-a-half LIM 2 decreases bone mineral content and bone mineral density in femur and tibia bones of female mice.
Four-and-a-half LIM 2 (FHL2) is a member of a family of LIM domain proteins which mediate protein-protein interactions. FHL2 acts as a coactivator and binds to important regulators of bone formation such as insulin-like growth factor binding protein (IGFBP)-5, androgen receptor, and beta-catenin. We hypothesized that FHL2 is an important regulator of bone formation. We evaluated growth and skeletal parameters in FHL2 knockout (KO) and wild-type (WT) mice at 4, 8, and 12 weeks of age. At 4 weeks of age, lack of FHL2 reduced femur, tibia, and total bone mineral content (BMC) and body weight in all mice. A gender-by-treatment interaction (P <or= 0.05) was observed for several parameters due to a greater reduction in females. Specifically, femur BMC was reduced 11-27% at 8 and 12 weeks of age and BMD was reduced 7-13% at all ages in female KO mice (P < 0.05). A similar reduction was observed in the tibias at 8 weeks of age. A 6% reduction (P = 0.07) in femur cortical thickness was observed at 12 weeks of age in female KO mice. Interestingly, a gender-specific reduction in IGFBP-5 expression was observed in the femurs of female KO mice. During differentiation of bone marrow stromal cells into osteoblasts, expression of osteocalcin, alkaline phosphatase, and bone sialoprotein was reduced 47-96% in FHL2 KO cells (P < 0.001). In conclusion, FHL2 is an important regulator of peak bone mass, lack of FHL2 produces gender- and site-specific effects on bone accretion and IGFBP-5 expression, and FHL2 is important for optimal osteoblast differentiation in vitro.
Govoni
K E
KE
Musculoskeletal Disease Center, 151, Jerry L. Pettis Memorial Veterans Affairs Medical Center, 11201 Benton Street, Loma Linda, CA 92357, USA.
Baylink
D J
DJ
Chen
J
J
Mohan
S
S
D000818:Animals; D015519:Bone Density; D001846:Bone Development; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation; D005260:Female; D005269:Femur / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology*; D010006:Osteoblasts / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013977:Tibia / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
C491382:Fhl2 protein, mouse; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D014157:Transcription Factors