The primary goal of this proposal is to determine the temporal and spatial regulation of bone acquisition by circulating insulin like growth factor-I (IGF-I). Several lines of evidence support the tenet that IGF-I has an important role in the process of bone remodeling. Human studies have demonstrated a relatively strong correlation between serum IGF-I and bone mineral density (BMD). Yet the precise mechanism and timing whereby circulating IGF-I exerts its influence on skeletal acquisition and maintenance have not been elucidated. Notwithstanding the remarkable progress in studying IGF-I action on bone, there are no studies that address the temporal role of circulating IGF-I. We previously generated liver specific IGF-I deficient (LID) mice using the Cre/LoxP system. LID mice exhibited a 75% reduction in serum IGF-I, accompanied by a fourfold increase in GH secretion, with no changes in IGF-I expression in extra-hepatic tissues. LID mice exhibit reductions in periosteal circumference, cortical thickness and total volumetric BMD. The LID mouse model established an essential role for endocrine IGF-I in skeletal integrity. However, there are limitations to this model: 1- IGF-I deficiency starts from birth;and 2- there is a profound and perpetual secondary increase in growth hormone. Thus, the developmental sequences and the anatomical changes in the skeleton of the growing and adult animal in response to changes in serum IGF-I are not clear. We have recently developed an inducible liver IGF-I deficient mouse model (iLID). The iLID model is based on the Cre/loxP system whereby the Cre recombinase is expressed specifically in the liver under the anti-trypsin-11 promoter, and can be induced by a single tamoxifen injection that does not otherwise affect the skeleton. This model permits us to dissect the temporal contribution of circulating IGF-I to skeletal acquisition and maintenance, and allows us to hypothesize that endocrine IGF-I differentially regulates bone formation and resorption during skeletal growth, adulthood and aging, primarily through its effects on osteoblast recruitment, differentiation and survival. Thus two major aims are proposed: 1-Determine the effect of serum IGF-I depletion during early growth, puberty, and post puberty (2,4,8, and 12 weeks) on peak bone acquisition. We will determine whether reductions in bone mass with IGF-I deletions are due to reduced accrual of bone or enhanced resorption. We will ascertain the peak time of IGF-I action on bone by utilizing the iLID mouse with temporal depletions at critical times of growth. 2-Determine the effect of temporal serum IGF-I depletion on bone maintenance in the adult mouse. We will define whether serum IGF-I deficiency in older mice leads to a reduction in trabecular thickness through alterations in bone formation, and determine whether this is due to reduced osteoprogenitor cells, altered osteoblast matrix synthesis, or early osteoblast apoptosis. We will deplete serum IGF-I at 16, 20, and 32 weeks, and examine the skeleton of the iLID mice up to 52 weeks.

Public Health Relevance

The primary goal of this proposal is to determine the temporal and spatial regulation of bone acquisition by circulating insulin like growth factor-I (IGF-I). We will capitalize on our recently developed tamoxifen inducible iLID model to determine, for the first time, the full developmental sequence of IGF-I deficiency in the growing and adult skeleton. The results of these studies will provide significant insight into the mechanisms of action of an essential regulatory pathway for optimal skeletal health and should determine whether reduced levels of serum IGF-I represent a risk for the impairment of peak bone acquisition and/or accelerated bone loss.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
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Sharrock, William J
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New York University
Other Basic Sciences
Schools of Dentistry
New York
United States
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Kennedy, Oran D; Sun, Hui; Wu, Yingjie et al. (2014) Skeletal response of male mice to anabolic hormone therapy in the absence of the Igfals gene. Endocrinology 155:987-99
Gong, Zhenwei; Kennedy, Oran; Sun, Hui et al. (2014) Reductions in serum IGF-1 during aging impair health span. Aging Cell 13:408-18
Gallagher, Emily Jane; Sun, Hui; Kornhauser, Caroline et al. (2014) The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes. Diabetes Metab Res Rev 30:191-200
Vijayakumar, Archana; Buffin, Nicholas J; Gallagher, Emily J et al. (2013) Deletion of growth hormone receptors in postnatal skeletal muscle of male mice does not alter muscle mass and response to pathological injury. Endocrinology 154:3776-83
Courtland, Hayden-William; Kennedy, Oran D; Wu, Yingjie et al. (2013) Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging. Age (Dordr) 35:1691-703
Wu, Yingjie; Sun, Hui; Basta-Pljakic, Jelena et al. (2013) Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor. J Bone Miner Res 28:1575-86
Yakar, Shoshana; Adamo, Martin L (2012) Insulin-like growth factor 1 physiology: lessons from mouse models. Endocrinol Metab Clin North Am 41:231-47, v
Elis, Sebastien; Wu, YingJie; Courtland, Hayden-William et al. (2011) Increased serum IGF-1 levels protect the musculoskeletal system but are associated with elevated oxidative stress markers and increased mortality independent of tissue igf1 gene expression. Aging Cell 10:547-50
Landau, Daniel; Biada, Jaclyn; Chen, Yu et al. (2011) A marked deficiency in circulating and renal IGF-I peptide does not inhibit compensatory renal enlargement in uninephrectomized mice. Growth Horm IGF Res 21:279-84
Courtland, Hayden-William; Sun, Hui; Beth-On, Mordechay et al. (2011) Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production. J Bone Miner Res 26:761-8

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