Combined Treatment With GH and IGF-I: Additive Effect on Cortical Bone Mass But Not on Linear Bone Growth in Female Rats

The growth-promoting effect of combined therapy with GH and IGF-I in normal rats is not known. We therefore investigated the efficacy of treatment with recombinant human (rh)GH and/or rhIGF-I on longitudinal bone growth and bone mass in intact, prepubertal, female Sprague-Dawley rats. rhGH was injected twice daily sc (5 mg/kg·d) and rhIGF-I continuously infused sc (2.2 or 4.4 mg/kg·d) for 28 days. Longitudinal bone growth was monitored by weekly x-rays of tibiae and nose-anus length measurements, and tibial growth plate histomorphology was analyzed. Bone mass was evaluated by peripheral quantitative computed tomography. In addition, serum levels of IGF-I, rat GH, acid labile subunit, IGF binding protein-3, 150-kDa ternary complex formation, and markers of bone formation and degradation were measured. Monotherapy with rhGH was more effective than rhIGF-I (4.4 mg/kg·d) to increase tibia and nose-anus length, whereas combined therapy did not further increase tibia, or nose-anus, lengths or growth plate height. In contrast, combined rhGH and rhIGF-I (4.4 mg/kg·d) therapy had an additive stimulatory effect on cortical bone mass vs rhGH alone. Combined treatment with rhGH and rhIGF-I resulted in markedly higher serum IGF-I concentrations vs rhGH alone but did not compromise the endogenous secretion of GH. We conclude that rhIGF-I treatment augments cortical bone mass but does not further improve bone growth in rhGH-treated young, intact, female rats.

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Astragalus Extract Mixture HT042 Improves Bone Growth, Mass, and Microarchitecture in Prepubertal Female Rats: A Microcomputed Tomographic Study

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/5219418 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7

Author(s):

Jungbin Song ◽

Sung Hyun Lee ◽

Donghun Lee ◽

Hocheol Kim

Keyword(s):

Bone Mass ◽

Cortical Bone ◽

Bone Growth ◽

Volume Fraction ◽

Control Diet ◽

Female Rats ◽

Volumetric Bone Mineral Density ◽

Mineral Density ◽

Longitudinal Bone Growth ◽

Tibial Length

Astragalus extract mixture HT042 is a standardized multiherbal mixture comprising Astragalus membranaceus, Eleutherococcus senticosus, and Phlomis umbrosa, which has proven to promote children’s height growth. The aim of this study was to investigate the effects of HT042 on longitudinal bone growth, bone mass, and bone microstructure in growing rats using a high-resolution microcomputed tomography system. Four-week-old female rats were fed an HT042-containing diet for 2 weeks. Tibial length was measured at baseline and weekly in vivo. At the end of the study, volumetric bone mineral density (vBMD) and microarchitectural parameters were estimated in the trabecular and cortical bone of the tibia. Tibial length gain was significantly increased by HT042 compared to that reported with the control diet. In the proximal tibial metaphysis, HT042-treated rats had significantly higher trabecular vBMD, bone volume fraction, and trabecular number and lower trabecular separation, trabecular pattern factor, and structure model index values than control rats did. Total cross-sectional area and bone area of the cortical bone in the tibial diaphysis also increased. These findings suggest that HT042 increases longitudinal bone growth rate, improves trabecular bone mass, and enhances the microarchitecture of trabecular and cortical bone during growth.

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Transverse Bone Growth and Cortical Bone Mass in the Human Prenatal Period

Neonatology ◽

10.1159/000243849 ◽

1992 ◽

Vol 62 (1) ◽

pp. 23-31 ◽

Cited By ~ 16

Author(s):

José Ignacio Rodríguez ◽

José Palacios ◽

Sebastián Rodríguez

Keyword(s):

Bone Mass ◽

Cortical Bone ◽

Bone Growth ◽

Prenatal Period ◽

Cortical Bone Mass

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Elevated Mechanical Loading When Young Provides Lifelong Benefits to Cortical Bone Properties in Female Rats Independent of a Surgically Induced Menopause

Endocrinology ◽

10.1210/en.2013-1227 ◽

2013 ◽

Vol 154 (9) ◽

pp. 3178-3187 ◽

Cited By ~ 13

Author(s):

Stuart J. Warden ◽

Matthew R. Galley ◽

Andrea L. Hurd ◽

Joseph M. Wallace ◽

Maxime A. Gallant ◽

...

Keyword(s):

Bone Mass ◽

Cortical Bone ◽

Bone Quality ◽

Female Rats ◽

Sprague Dawley ◽

Bone Properties ◽

Skeletal Loading ◽

Cortical Bone Mass ◽

Independent Effects ◽

Surgically Induced

Exercise that mechanically loads the skeleton is advocated when young to enhance lifelong bone health. Whether the skeletal benefits of elevated loading when young persist into adulthood and after menopause are important questions. This study investigated the influence of a surgically induced menopause in female Sprague-Dawley rats on the lifelong maintenance of the cortical bone benefits of skeletal loading when young. Animals had their right forearm extrinsically loaded 3 d/wk between 4 and 10 weeks of age using the forearm axial compression loading model. Left forearms were internal controls and not loaded. Animals were subsequently detrained (restricted to cage activities) for 94 weeks (until age 2 years), with ovariectomy (OVX) or sham-OVX surgery being performed at 24 weeks of age. Loading enhanced midshaft ulna cortical bone mass, structure, and estimated strength. These benefits persisted lifelong and contributed to loaded ulnas having greater strength after detraining. Loading also had effects on cortical bone quality. The benefits of loading when young were not influenced by a surgically induced menopause because there were no interactions between loading and surgery. However, OVX had independent effects on cortical bone mass, structure, and estimated strength at early postsurgery time points (up to age 58 weeks) and bone quality measures. These data indicate skeletal loading when young had lifelong benefits on cortical bone properties that persisted independent of a surgically induced menopause. This suggests that skeletal loading associated with exercise when young may provide lifelong antifracture benefits by priming the skeleton to offset the cortical bone changes associated with aging and menopause.

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Prostaglandin E2 enhances cortical bone mass and activates intracortical bone remodeling in intact and ovariectomized female rats

Bone ◽

10.1016/8756-3282(90)90078-d ◽

1990 ◽

Vol 11 (4) ◽

pp. 253-266 ◽

Cited By ~ 193

Author(s):

W.S.S. Jee ◽

S. Mori ◽

X.J. Li ◽

S. Chan

Keyword(s):

Bone Mass ◽

Prostaglandin E2 ◽

Cortical Bone ◽

Bone Remodeling ◽

Female Rats ◽

Cortical Bone Mass

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IL-23 receptor deficiency results in lower bone mass via indirect regulation of bone formation

Scientific Reports ◽

10.1038/s41598-021-89625-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wida Razawy ◽

Celso H. Alves ◽

Marijke Koedam ◽

Patrick S. Asmawidjaja ◽

Adriana M. C. Mus ◽

...

Keyword(s):

Bone Formation ◽

Bone Mass ◽

Cortical Bone ◽

Bone Growth ◽

Osteoclast Differentiation ◽

Bone Homeostasis ◽

Littermate Control ◽

Cortical Bone Mass

AbstractThe IL-23 receptor (IL-23R) signaling pathway has pleiotropic effects on the differentiation of osteoclasts and osteoblasts, since it can inhibit or stimulate these processes via different pathways. However, the potential role of this pathway in the regulation of bone homeostasis remains elusive. Therefore, we studied the role of IL-23R signaling in physiological bone remodeling using IL-23R deficient mice. Using µCT, we demonstrate that 7-week-old IL-23R−/− mice have similar bone mass as age matched littermate control mice. In contrast, 12-week-old IL-23R−/− mice have significantly lower trabecular and cortical bone mass, shorter femurs and more fragile bones. At the age of 26 weeks, there were no differences in trabecular bone mass and femur length, but most of cortical bone mass parameters remain significantly lower in IL-23R−/− mice. In vitro osteoclast differentiation and resorption capacity of 7- and 12-week-old IL-23R−/− mice are similar to WT. However, serum levels of the bone formation marker, PINP, are significantly lower in 12-week-old IL-23R−/− mice, but similar to WT at 7 and 26 weeks. Interestingly, Il23r gene expression was not detected in in vitro cultured osteoblasts, suggesting an indirect effect of IL-23R. In conclusion, IL-23R deficiency results in temporal and long-term changes in bone growth via regulation of bone formation.

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Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth

Journal of Endocrinology ◽

10.1677/joe.0.1800247 ◽

2004 ◽

Vol 180 (2) ◽

pp. 247-255 ◽

Cited By ~ 122

Author(s):

J Wang ◽

J Zhou ◽

CM Cheng ◽

JJ Kopchick ◽

CA Bondy

Keyword(s):

Growth Hormone ◽

Growth Plate ◽

Bone Growth ◽

Long Bone ◽

Null Mouse ◽

Chondrocyte Proliferation ◽

Chondrocyte Hypertrophy ◽

Longitudinal Bone Growth ◽

Germinal Zone ◽

Igf I

The possibility that growth hormone (GH) has effects on long bone growth independent of insulin-like growth factor-I (IGF-I) has long been debated. If this is true, then long bone growth should be more profoundly affected by the absence of GH (since both GH and GH-stimulated IGF-I effects are absent) than by the absence of IGF-I alone (since GH is still present and actually elevated). To test this hypothesis, we compared long bone growth in mice with targeted deletions of Igf1 vs growth hormone receptor (Ghr). Tibial linear growth rate was reduced by approximately 35% in Igf1 null mice and by about 65% in Ghr null mice between postnatal days 20 and 40, a time of peak GH effect during normal longitudinal growth. The Igf1 null mouse growth plate demonstrated significant enlargement of the germinal zone; chondrocyte proliferation and numbers were normal but chondrocyte hypertrophy was significantly reduced. In contrast, the Ghr null mouse germinal zone was hypoplastic, chondrocyte proliferation and numbers were significantly reduced, and chondrocyte hypertrophy was also reduced. We have previously demonstrated that IGF-II is highly expressed in growth plate germinal and proliferative zones, so we considered the possibility that GH-stimulated IGF-II production might promote germinal zone expansion and maintain normal proliferation in the Igf1 null mouse growth plate. Supporting this view, IGF-II mRNA was increased in the Igf1 null mouse and decreased in the Ghr null mouse growth plate.Thus, in the complete absence of IGF-I but in the presence of elevated GH in the Igf1 null mouse, reduction in chondrocyte hypertrophy appears to be the major defect in longitudinal bone growth. In the complete absence of a GH effect in the Ghr null mouse, however, both chondrocyte generation and hypertrophy are compromised, leading to a compound deficit in long bone growth. These observations support dual roles for GH in promoting longitudinal bone growth: an IGF-I-independent role in growth plate chondrocyte generation and an IGF-I-dependent role in promoting chondrocyte hypertrophy. The question of whether GH has direct effects on chondrocyte generation is still not settled, however, since it now appears that IGF-II may medicate some of these effects on the growth plate.

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Perinatal Maternal Dietary Supplementation of ω3-Fatty Acids Transiently Affects Bone Marrow Microenvironment, Osteoblast and Osteoclast Formation, and Bone Mass in Male Offspring

Endocrinology ◽

10.1210/en.2011-1917 ◽

2012 ◽

Vol 153 (5) ◽

pp. 2455-2465 ◽

Cited By ~ 17

Author(s):

Laura Fong ◽

Beverly S. Muhlhausler ◽

Robert A. Gibson ◽

Cory J. Xian

Keyword(s):

Fatty Acids ◽

Bone Mass ◽

Growth Plate ◽

Bone Health ◽

Bone Growth ◽

Nuclear Factor Κb ◽

Female Offspring ◽

Osteoclast Formation ◽

Female Rats ◽

Chow Diet

It is increasingly evident that micronutrient environment experienced before birth and in infancy is important for achieving optimal bone mass by adolescence and maintaining bone health. This study determined whether maternal supplementation with ω3-polyunsaturated fatty acids (n3FA) improved offspring bone growth and adult bone mass. Female rats were fed a diet containing 0.1% (control, n = 10) or 1% (n3FA, n = 11) docosahexanoic acid (DHA) during pregnancy and lactation. Offspring were weaned onto a control rat chow diet. Tibial growth plate and metaphysis structure, osteoblast/osteoclast density and differentiation, and gene expression were assessed in offspring at 3 wk (weaning), 6 wk (adolescent), and 3 months (adult). Maternal n3FA supplementation elevated offspring plasma n3FA levels at 3 and 6 wk. Although total growth plate heights were unaffected at any age, the resting zone thickness was increased in both male and female offspring at 3 wk. In n3FA males, but not females, bone trabecular number and thickness were increased at 3 wk but not other ages. The wk 3 n3FA males also exhibited an increased bone volume, an increased osteoblast but decreased osteoclast density, and lower expression of osteoclastogenic cytokines receptor activator of nuclear factor-κB ligand, TNF-α, and IL-6. No effects were seen at 6 wk or 3 months in either sex. Thus, perinatal n3FA supplementation is associated with increased bone formation, decreased resorption, and a higher bone mass in males, but not in females, at weaning; these effects do not persist into adolescence and adulthood and are unlikely to produce lasting improvements in bone health.

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