Insulin-like growth factor regulates peak bone mineral density in mice by both growth hormone-dependent and -independent mechanisms.
To evaluate the relative contribution of the GH/IGF axis to the development of peak bone mineral density (BMD), we measured skeletal changes in IGF-I knockout (KO), IGF-II KO, and GH-deficient lit/lit mice and their corresponding control mice at d 23 (prepubertal), 31 (pubertal), and 56 (postpubertal) in the entire femur by dual energy x-ray absorptiometry and in the mid-diaphysis by peripheral quantitative computed tomography. Lack of growth factors resulted in different degrees of failure of skeletal growth depending on the growth period and the growth factor involved. At d 23, femoral length, size, and BMD were reduced by 25-40%, 15-17%, and 8-10%, respectively, in mice deficient in IGF-I, IGF-II, and GH compared with the control mice. During puberty, BMD increased by 40% in control mice and by 15% in IGF-II KO and GH-deficient mice, whereas it did not increase in the IGF-I KO mice. Disruption of IGF-I, but not IGF-II, completely prevented the periosteal expansion that occurs during puberty, whereas it was reduced by 50% in GH-deficient mice. At d 56, femoral length, size, and BMD were reduced by 40-55%, 11-18%, and 25-32%, respectively, in mice deficient in IGF-I, IGF-II, and GH compared with the control mice. Our data demonstrate that: 1) mice deficient in IGF-I exhibit a greater impairment in bone accretion than mice deficient in IGF-II or GH; 2) GH/IGF-I, but not IGF-II, is critical for puberty-induced bone growth; and 3) IGF-I effects on bone accretion during prepuberty are mediated predominantly via mechanisms independent of GH, whereas during puberty they are mediated via both GH-dependent and GH-independent mechanisms.
Mohan
Subburaman
S
Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center and Department of Medicine, Loma Linda University, Loma Linda, California, USA. Subburaman.Mohan@med.va.gov
Richman
Charmaine
C
Guo
Rongqing
R
Amaar
Yousef
Y
Donahue
Leah Rea
LR
Wergedal
Jon
J
Baylink
David J
DJ
D015502:Absorptiometry, Photon; D000818:Animals; D001835:Body Weight; D015519:Bone Density; D005260:Female; D005269:Femur / Q000033:anatomy & histology; D013006:Growth Hormone / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009929:Organ Size; D015675:Osteocalcin / Q000097:blood; D012727:Sex Characteristics; D012741:Sexual Maturation; D014057:Tomography, X-Ray Computed
D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone