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 Ca2+/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.
Highlights
Mechanical stimuli are anabolic for bone and hold promise to counteract skeletal fragility associated with bone loss pathologies [1,2]
In part due to deficits in how cells within bone respond to skeletal loading, readily complied exercise has proved ineffective in enhancing bone mass in the elderly
We examined whether the ability of physical exercise to increase bone mass can be restored at advanced age
Summary
Mechanical stimuli are anabolic for bone and hold promise to counteract skeletal fragility associated with bone loss pathologies [1,2]. Readily complied and tolerated exercise has proved ineffective in enhancing bone mass in the elderly population most in need of such interventions [4,5]. Studies that have examined the apparent ineffectiveness of mild exercise in the elderly using cell culture systems and animal models have sometimes led to conflicting outcomes. Reports suggest that exercise training can elicit enhanced bone tissue responses in animals at advanced age [8,9]. In studies where in vivo deformations and strains induced by mechanical stimuli are equivalently calibrated, observations suggest that aging markedly blunts the osteogenic response to mechanical stimuli [10,11], and renders adaptation into a low-level binary off-on state [12]
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