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 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.

Biomechanical forces in the skeleton and their relevance to bone metastasis: Biology and engineering considerations

“…For example, inserting ~10 seconds of either zero or low magnitude load in between single loading bouts amplified bone formation in two different in vivo loading models [133, 134]. Importantly, this technique lowered the strain magnitude required for activating bone formation as well as returned loading sensitivity to senescent mice [135, 136]. Whether or not these principles have any direct bearing on bone metastatic tumor progression or tumor cell function has not been explored.…”

Mechanosignaling in Bone Health, Trauma and Inflammation

“…The importance of mechanical load is further underscored by the observations that reduced physical demands or disuse of bones leads to rapid bone loss and skeletal fragility and osteopenia generally observed in aging, spinal cord injuries, prolonged bed rest, and microgravity (9,84,86,89,120,122). Conversely, physiological loading of the skeleton is anabolic and stimulates osteogenesis; hence, acting as an important therapeutic signal in diseases associated with inflammation, osteopenia, osteoporosis, and arthritis (8,85,107,120,121). Clinically, it is well documented that appropriate exercise is beneficial not only for arthritic diseases of the joints involving cartilage and bone damage, but also for systemic diseases, such as systemic lupus erythematous and diabetes (76,109).…”

Rodent Models of Aging Bone: An Update

“…Although in an axially loaded mouse tibia model the interaction between the zoledronate and loading seemed to suggest a negative interaction especially at high levels of applied strain [71], supplementing mechanical stimuli with low-dose cyclosporine A seemed to be beneficial to the senescent skeleton and may augment bone mass [72]. It therefore seems reasonable to suggest that more studies are needed to better understand the relationship between these pathways.…”

“…Along the same lines, interactions of pharmaceutical agents such as zoledronate, a bisphosphonate [71], and cyclosporine A [72] have been studied in mice, which have been mechanically loaded to test the potential interactions between the two regimens. Although in an axially loaded mouse tibia model the interaction between the zoledronate and loading seemed to suggest a negative interaction especially at high levels of applied strain [71], supplementing mechanical stimuli with low-dose cyclosporine A seemed to be beneficial to the senescent skeleton and may augment bone mass [72].…”