IGF-1 Signaling is Essential for Differentiation of Mesenchymal Stem Cells for Peak Bone Mass

作     者：Janet L. Crane Luo Zhao Joseph S. Frye Lingling Xian Tao Qiu Xu Cao 

作者机构：Department of PediatricsJohns Hopkins University School of Medicine Department of Orthopaedic SurgeryJohns Hopkins University School of Medicine Department of OrthopedicsPeking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical Sciences University of Missouri School of Medicine 

出 版 物：《Bone Research》 (骨研究（英文版）)

年 卷 期：2013年第1卷第2期

页      面：186-194页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100202[医学-儿科学] 10[医学] 

基　　金：supported in part by the grants from the United States National Institute of Health NIDDK including T32DK07751 (JLC) the Diabetes Research and Training Center grant P60DK079637(JSF),and DK057501 and DK08098 (XC) 

主　　题：osteoblasts knockout mice cell migration IGF receptor nestin 

摘      要：Survival of children with chronic medical illnesses is leading to an increase in secondary osteoporosis due to impaired peak bone mass （PBM）. Insulin-like growth factor type Ⅰ （IGF-1） levels correlate with the pattern of bone mass accrual and many chronic illnesses are associated with low IGF-1 levels. Reduced serum levels of IGF-1 minimally affect the integrity of the skeleton, whereas recent studies suggest that skeletal IGF-I regulates PBM. To determine the role of IGF-1 in postnatal bone mass accrual regardless of source, we established an inducible type 1 Igf receptor Cre/lox knockout mouse model, in which the type 1 Igf receptor was deleted inducibely in the mesenchymal stem cells （MSCs） from 3-7 weeks of age. The size of the mouse was not affected as knockout and wild type mice had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type controls, indicating that IGF-1 is critical for bone mass. IGF-1 signaling in MSCs in vitro has been implicated to be involved in both migration to the bone surface and differentiation into bone forming osteoblasts. To clarify the exact role of IGF-1 in bone, we found by immunohistochemical analysis that a similar number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantly, 56% fewer osteocalcin-positive mature osteoblasts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wild type littermates. These in vivo data demonstrate that the primary role of skeletal IGF-1 is for the terminal differentiation of osteoprogenitors, but refute the role of IGF-1 in MSC migration in vivo. Additionally, these findings confirm that impaired IGF-1 signaling in bone MSCs is sufficient to impair bone mass acquisition.