IGF-1 Signaling is Essential for Differentiation of Mesenchymal Stem Cells for Peak Bone Mass.
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 1 (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.
Department of Pediatrics, Johns Hopkins University School of Medicine , Baltimore, MD 21205, USA ; Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore. MD 21205, USA.
Janet L
JL
Crane
Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing. 100730, P.R. China.
Luo
L
Zhao
University of Missouri School of Medicine , Columbia, MO, 65211, USA.
Joseph S
JS
Frye
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore. MD 21205, USA.
Lingling
L
Xian
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore. MD 21205, USA.
Tao
T
Qiu
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine , Baltimore. MD 21205, USA.
Xu
X
Cao
IGF receptor; cell migration; knockout mice; nestin; osteoblasts