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.
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.
|Gong, Zhenwei; Kennedy, Oran; Sun, Hui et al. (2014) Reductions in serum IGF-1 during aging impair health span. Aging Cell 13:408-18|
|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|
|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|
|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|
|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|
|Elis, Sebastien; Wu, Yingjie; Courtland, Hayden-William et al. (2011) Unbound (bioavailable) IGF1 enhances somatic growth. Dis Model Mech 4:649-58|
|Elis, Sebastien; Courtland, Hayden-William; Wu, Yingjie et al. (2010) Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1. J Bone Miner Res 25:1257-66|
|Yakar, Shoshana; Courtland, Hayden-William; Clemmons, David (2010) IGF-1 and bone: New discoveries from mouse models. J Bone Miner Res 25:2543-52|
|Fritton, J Christopher; Kawashima, Yuki; Mejia, Wilson et al. (2010) The insulin-like growth factor-1 binding protein acid-labile subunit alters mesenchymal stromal cell fate. J Biol Chem 285:4709-14|
|Fritton, J Christopher; Emerton, Kelly B; Sun, Hui et al. (2010) Growth hormone protects against ovariectomy-induced bone loss in states of low circulating insulin-like growth factor (IGF-1). J Bone Miner Res 25:235-46|
Showing the most recent 10 out of 18 publications