Skeletal unloading results in a cessation in bone formation and an initial increase in bone resorption. These changes are accompanied by resistance to the anabolic actions of insulin like growth factor 1 (IGF1) on bone. On the other hand skeletal loading increases IGF1 production, and enhances IGF1 activation of IGF1R as part of the mechanism by which it increases bone formation. In seeking a mechanism for the load induced regulation of IGF1 signaling we discovered that skeletal unloading was associated with a decrease in the expression of integrins, in particular integrins with b1 (IGTB1) and b3 (ITGB3) subunits. We discovered that in osteoblasts, IGF1 increased the binding of ITGB3 to IGF1R, and that if ITGB3 were downregulated, IGF1 could no longer activate IGF1R. Focal adhesion kinase (FAK) and/or its related family member protein tyrosine kinase 2 beta (PTK2B) provide a link between the integrin and growth factor receptor pathways including between ITGB3 and IGF1R. IGF1 activation of IGF1R results in phosphorylation (presumed activation) of FAK, whereas inhibition of FAK blocks activation of IGF1R either by IGF1 or by load. To test the role of IGF1 signaling directly in vivo we developed mice in which the IGF1R was deleted in mature osteoblasts and examined whether this mouse would respond to skeletal unloading or reloading. Mice lacking IGF1R showed an equivalent decrease in bone formation during unloading to controls, but failed to increase bone formation during reloading. The striking result, however, was that this failure to respond to reloading was found only in periosteal bone formation; endosteal and trabecular bone formation responded comparable to controls. These results focused our attention on the periosteum where the osteoprogenitors are exposed not only to load induced IGF1 emanating from both osteocytes and muscle, but to the integrin ligand periostin, a combination we hypothesize will maximize their proliferation, differentiation, and formation of new bone in response to mechanical load. In this project we will test the hypothesis that skeletal loading stimulates IGF1 production in osteocytes and muscle and formation of the IGF1R/integrin complex in periosteal osteoprogenitors (pOP) required for the IGF1 mediated anabolic response of these cells to load. This will be achieved in the following three aims:
Aim1 --Determine the components of the IGF1R complex that forms in response to load and/or IGF1 in periosteal cells in vitro, and assess their role in contributing to that response;
Aim 2 -- Determin the impact of deleting Igf1r and Itgb3 from pOP in vivo with respect to their ability to mediate th skeletal response to load;
Aim 3 --Determine the source(s) of IGF1 facilitating load induced periosteal bone formation with particular attention to osteocytes and muscle. We will be utilizing novel animal models and state of the art techniques to fulfill these aims. The results will provide new understanding of how IGF1/integrin signaling interactions regulate the skeletal response to mechanical load, open up new avenues for further investigation, and provide potential targets for preventing the bone loss of immobilization and aging.

Public Health Relevance

The mechanisms underlying periosteal bone formation remain unclear. We have found that the deletion of IGF1 from mature osteoblasts/osteocytes disrupts periosteal bone formation in response to load but not that of trabecular or endosteal bone formation, a response involving integrins. Using cell specific deletion of the IGF1 receptor (IGF1R) and ITGB3, we plan to examine the contribution IGF1 and integrins make to mechanism by which periosteal cells respond to load.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055924-09
Application #
9416921
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Alekel, D Lee
Project Start
2008-04-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Tian, Faming; Wang, Yongmei; Bikle, Daniel D (2017) IGF-1 signaling mediated cell-specific skeletal mechano-transduction. J Orthop Res :
Wang, Tao; Zhang, Xinping; Bikle, Daniel D (2017) Osteogenic Differentiation of Periosteal Cells During Fracture Healing. J Cell Physiol 232:913-921
Tahimic, Candice G T; Long, Roger K; Kubota, Takuo et al. (2016) Regulation of Ligand and Shear Stress-induced Insulin-like Growth Factor 1 (IGF1) Signaling by the Integrin Pathway. J Biol Chem 291:8140-9
Babey, Muriel; Wang, Yongmei; Kubota, Takuo et al. (2015) Gender-Specific Differences in the Skeletal Response to Continuous PTH in Mice Lacking the IGF1 Receptor in Mature Osteoblasts. J Bone Miner Res 30:1064-76
Wang, Tao; Wang, Yongmei; Menendez, Alicia et al. (2015) Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing. J Bone Miner Res 30:1572-84
Wang, Yongmei; Menendez, Alicia; Fong, Chak et al. (2015) IGF-I Signaling in Osterix-Expressing Cells Regulates Secondary Ossification Center Formation, Growth Plate Maturation, and Metaphyseal Formation During Postnatal Bone Development. J Bone Miner Res 30:2239-48
Shah, Arti D; Hsiao, Edward C; O'Donnell, Betsy et al. (2015) Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D3 Catabolism in a Patient With CYP24A1 Mutations. J Clin Endocrinol Metab 100:2832-6
Jiang, Yan J; Bikle, Daniel D (2014) LncRNA profiling reveals new mechanism for VDR protection against skin cancer formation. J Steroid Biochem Mol Biol 144 Pt A:87-90
Wang, Yongmei; Menendez, Alicia; Fong, Chak et al. (2014) Ephrin B2/EphB4 mediates the actions of IGF-I signaling in regulating endochondral bone formation. J Bone Miner Res 29:1900-13
Jiang, Yan J; Bikle, Daniel D (2014) LncRNA: a new player in 1?, 25(OH)(2) vitamin D(3) /VDR protection against skin cancer formation. Exp Dermatol 23:147-50

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