Osteoporosis is a major bone disorder that affects both men and women during aging. The pathogenesis is not only due to the increased osteoclast activity in bone resorption, but also a decrease in bone formation mostly attributed to an insufficient supply of osteoblasts in the aged. Osteoblasts are non-replicative cells derived from the mesenchymal stem cell (MSC) lineage. We hypothesize that the pattern of acquisition of bone mass during childhood, maintenance in adulthood, and loss with aging is due to decreased osteoblast availability for bone formation as MSCs lose/slow their ability to differentiate into osteoblasts with aging. Insulin like growth factor type 1 (IGF-1) is known to stimulate osteoblastic differentiation by activation of mammalian target of rapamycin to maintain proper bone microarchitecture and mass. Thus, a series of experiments and animal models are designed to confirm the hypothesis that MSC differentiation slows with aging, mediated by down- regulation of the IGF-1 signaling pathway.
The first aim i s to determine the temporal-spatial regulation of MSC differentiation into mature osteoblasts in young, adult, and old mice using a MSC lineage tracing mouse model.
The second aim i s to dissect how the IGF-1 signaling pathway is regulated during the lifespan and affects the fate of MSCs. The goal of the proposed study is to identify the rate limiting steps in the differentiation process so that future therapies can be targeted at these essential steps. This project will be conducted by Dr. Janet Crane under the guidance of Dr. Xu Cao in the Department of Orthopaedic Surgery at Johns Hopkins University. Dr. Crane, a Pediatric Endocrinologist, is dedicated to a career in academia using basic and translational research to study factors affecting bone formation. Dr. Cao has an exceptional research career in bone biology using in vivo mouse models to study signaling mechanisms by which bone marrow MSCs contribute to bone homeostasis and remodeling, which will provide Dr. Crane with the training necessary to initiate her career as an independent investigator. The available resources and strong ongoing collaborative arrangements within the Department of Orthopaedic Surgery, the Division of Pediatric Endocrinology, and the Department of Neuroscience provide a rich learning environment and are completely supportive of the academic advancement of Dr. Crane.

Public Health Relevance

There are limited treatment options for osteoporosis that build bone. Understanding the mechanisms that affect the ability of mesenchymal stem cells to become bone forming cells (mature osteoblasts) will identify targets for the development of future anabolic therapies.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Nicks, Kristy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Wang, Xiao; Li, Fengfeng; Xie, Liang et al. (2018) Inhibition of overactive TGF-? attenuates progression of heterotopic ossification in mice. Nat Commun 9:551
Wang, Xiao; Xie, Liang; Crane, Janet et al. (2018) Aberrant TGF-? activation in bone tendon insertion induces enthesopathy-like disease. J Clin Invest 128:846-860
Yang, Ping; Lv, Shan; Wang, Yan et al. (2018) Preservation of type H vessels and osteoblasts by enhanced preosteoclast platelet-derived growth factor type BB attenuates glucocorticoid-induced osteoporosis in growing mice. Bone 114:1-13
Qiu, Tao; Crane, Janet L; Xie, Liang et al. (2018) IGF-I induced phosphorylation of PTH receptor enhances osteoblast to osteocyte transition. Bone Res 6:5
Xu, Xin; Zheng, Liwei; Yuan, Quan et al. (2018) Transforming growth factor-? in stem cells and tissue homeostasis. Bone Res 6:2
Bian, Qin; Ma, Lei; Jain, Amit et al. (2017) Mechanosignaling activation of TGF? maintains intervertebral disc homeostasis. Bone Res 5:17008
Yang, Ping; Chen, Na; Yang, Dongyun et al. (2017) The ratio of serum Angiopoietin-1 to Angiopoietin-2 in patients with cervical cancer is a valuable diagnostic and prognostic biomarker. PeerJ 5:e3387
Li, Changjun; Chai, Yu; Wang, Lei et al. (2017) Programmed cell senescence in skeleton during late puberty. Nat Commun 8:1312
Bian, Qin; Jain, Amit; Xu, Xin et al. (2016) Excessive Activation of TGF? by Spinal Instability Causes Vertebral Endplate Sclerosis. Sci Rep 6:27093
Li, Changjun; Zhen, Gehua; Chai, Yu et al. (2016) RhoA determines lineage fate of mesenchymal stem cells by modulating CTGF-VEGF complex in extracellular matrix. Nat Commun 7:11455

Showing the most recent 10 out of 16 publications