title: Rescuing loading induced bone formation at senescence.
abstract: The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca(2+)/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential.
authors.affiliation: Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America. sundars@u.washington.edu
authors.forename: Sundar
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Ausk
authors.forename: Jitendra
authors.initials: J
authors.lastname: Prasad
authors.forename: Dewayne
authors.initials: D
authors.lastname: Threet
authors.forename: Steven D
authors.initials: SD
authors.lastname: Bain
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Richardson
authors.forename: Ted S
authors.initials: TS
authors.lastname: Gross
mesh_terms: D000375:Aging / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001696:Biomechanical Phenomena / Q000502:physiology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D019295:Computational Biology / Q000379:methods*; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism; D010011:Osteocytes / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D010024:Osteoporosis / Q000473:pathology; D015203:Reproducibility of Results; D013977:Tibia / Q000166:cytology; D016474:Weight-Bearing / Q000502:physiology*
chemical_list: D050778:NFATC Transcription Factors; D016572:Cyclosporine; D002118:Calcium