Insulin-Like Growth Factor-I Is Essential for Embryonic Bone Development

Hospital for Special Surgery, New York, New York, United States
Endocrinology (Impact Factor: 4.5). 11/2006; 147(10):4753-61. DOI: 10.1210/en.2006-0196
Source: PubMed


Although IGF-I has been identified as an important growth factor for the skeleton, the role of IGF-I on embryonic bone development remains unknown. Here we show that, in IGF-I-deficient (IGF-I(-/-)) mice, skeletal malformations, including short-limbed dwarfism, were evident at days post coitus (dpc) 14.5 to 18.5, accompanied by delays of mineralization in the spinal column, sternum, and fore paws. Reduced chondrocyte proliferation and increased chondrocyte apoptosis were identified in both the spinal ossification center and the growth plate of long bones. Abnormal chondrocyte differentiation and delayed initiation of mineralization was characterized by small size and fewer numbers of type X collagen expressing hypertrophic chondrocytes and lower osteocalcin expression. The Indian hedgehog-PTHrP feedback loop was altered; expression of Indian hedgehog was reduced in IGF-I(-/-) mice in long bones and in the spine, whereas expression of PTHrP was increased. Our results indicate that IGF-I plays an important role in skeletal development by promoting chondrocyte proliferation and maturation while inhibiting apoptosis to form bones of appropriate size and strength.

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Available from: Hashem Elalieh, Apr 15, 2014
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    • "Two growth factors that seem particularly important for differentiation towards IVD-like cells are IGF-1 and TGF-β1. IGF-1 and its receptor have been shown to be expressed in the IVD [57,58], and IGF-1 has been shown to have an effect on early dorso-anterior (notochord) development [59] and to promote chondrocyte differentiation and embryonic bone development [60]. Members of the TGF-β family and receptors are expressed in the IVD [57,58], and TGF-β1 was reported to be able to induce rat MSCs to differentiation to a phenotype consistent with NP on alginate hydrogels [19]. "
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    ABSTRACT: Cell supplementation to the herniated or degenerated intervertebral disc (IVD) is a potential strategy to promote tissue regeneration and slow disc pathology. Human umbilical cord mesenchymal stromal cells (HUCMSCs) - originating from the Wharton's jelly - remain an attractive candidate for such endeavors with their ability to differentiate into multiple lineages. Previously, mesenchymal stem cells (MSCs) have been studied as a potential source for disc tissue regeneration. However, no studies have demonstrated that MSCs can regenerate matrix with unique characteristics matching that of immature nucleus pulposus (NP) tissues of the IVD. In our prior work, immature NP cells were found to express specific laminin isoforms and laminin-binding receptors that may serve as phenotypic markers for evaluating MSC differentiation to NP-like cells. The goal of this study is to evaluate these markers and matrix synthesis for HUCMSCs cultured in a laminin-rich pseudo-three-dimensional culture system. HUCMSCs were seeded on top of Transwell inserts pre-coated with Matrigel™, which contained mainly laminin-111. Cells were cultured under hypoxia environment with three differentiation conditions: NP differentiation media (containing 2.5% Matrigel™ solution to provide for a pseudo-three-dimensional laminin culture system) with no serum, or the same media supplemented with either insulin-like growth factor-1 (IGF-1) or transforming growth factor-β1 (TGF-β1). Cell clustering behavior, matrix production and the expression of NP-specific laminin and laminin-receptors were evaluated at days 1, 7, 13 and 21 of culture. Data show that a pseudo-three-dimensional culture condition (laminin-1 rich) promoted HUCMSC differentiation under no serum conditions. Starting at day 1, HUCMSCs demonstrated a cell clustering morphology similar to that of immature NP cells in situ and that observed for primary immature NP cells within the similar laminin-rich culture system (prior study). Differentiated HUCMSCs under all conditions were found to contain glycosaminoglycan, expressed extracellular matrix proteins of collagen II and laminin α5, and laminin receptors (integrin α3 and β4 subunits). However, neither growth factor treatment generated distinct differences in NP-like phenotype for HUCMSC as compared with no-serum conditions. HUCMSCs have the potential to differentiate into cells sharing features with immature NP cells in a laminin-rich culture environment and may be useful for IVD cellular therapy.
    Stem Cell Research & Therapy 10/2013; 4(5):120. DOI:10.1186/scrt331 · 3.37 Impact Factor
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    • "As expected, BMP-2 expression particularly in hypertrophic chondrocytes of the growth plate was increased in the laser acupuncture-treated group compared with the control group (Figure 4(a), arrow denotes brown staining indicative of BMP-2 expression). IGF-1 is an important factor to augment longitudinalbone growth by stimulating growth plate chondrocyte proliferation [25]. IGF-1 immunostaining was relatively higher in the proliferative zone than the hypertrophic zone. "
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    ABSTRACT: Longitudinal bone growth is the results of chondrocyte proliferation and hypertrophy and subsequent endochondral ossification in the growth plate. Recently, laser acupuncture (LA), an intervention to stimulate acupoint with low-level laser irradiation, has been suggested as an intervention to improve the longitudinal bone growth. This study investigated the effects of laser acupuncture on growth, particularly longitudinal bone growth in adolescent male rats. Laser acupuncture was performed once every other day for a total of 9 treatments over 18 days to adolescent male rats. Morphometry of the growth plate, longitudinal bone growth rate, and the protein expression of BMP-2 and IGF-1 in growth plate were observed. The bone growth rate and the heights of growth plates were significantly increased by laser acupuncture. BMP-2 but not IGF-1 immunostaining in growth plate was increased as well. In conclusion, LA promotes longitudinal bone growth in adolescent rats, suggesting that laser acupuncture may be a promising intervention for improving the growth potential for children and adolescents.
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    • "IGF-1 plays an important role in skeletal development and normal postnatal growth (43). IGF-1 deficiency in mice results in marked skeletal dysplasia and growth retardation (44). Thus, the lower level of serum IGF-1 in LKB1ad−/− mice may contribute to their small skeleton size and growth retardation. "
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