Distinct Cyclosporin A Doses Are Required to Enhance Bone Formation Induced by Cyclic and Rest-Inserted Loading in the Senescent Skeleton

Abstract

Age-related decline in periosteal adaptation negatively impacts the ability to utilize exercise to enhance bone mass and strength in the elderly. We recently observed that in senescent animals subject to cyclically applied loading, supplementation with Cyclosporin A (CsA) substantially enhanced the periosteal bone formation rates to levels observed in young animals. We therefore speculated that if the CsA supplement could enhance bone response to a variety of types of mechanical stimuli, this approach could readily provide the means to expand the range of mild stimuli that are robustly osteogenic at senescence. Here, we specifically hypothesized that a given CsA supplement would enhance bone formation induced in the senescent skeleton by both cyclic (1-Hz) and rest-inserted loading (wherein a 10-s unloaded rest interval is inserted between each load cycle). To examine this hypothesis, the right tibiae of senescent female C57BL/6 mice (22 Mo) were subjected to cyclic or rest-inserted loading supplemented with CsA at 3.0 mg/kg. As previously, we initially found that while the periosteal bone formation rate (p.BFR) induced by cyclic loading was enhanced when supplemented with 3.0 mg/kg CsA (by 140%), the response to rest-inserted loading was not augmented at this CsA dosage. In follow-up experiments, we observed that while a 30-fold lower CsA dosage (0.1 mg/kg) significantly enhanced p.BFR induced by rest-inserted loading (by 102%), it was ineffective as a supplement with cyclic loading. Additional experiments and statistical analysis confirmed that the dose-response relations were significantly different for cyclic versus rest-inserted loading, only because the two stimuli required distinct CsA dosages for efficacy. While not anticipated a priori, clarifying the complexity underlying the observed interaction between CsA dosage and loading type holds potential for insight into how bone response to a broad range of mechanical stimuli may be substantially enhanced in the senescent skeleton.

An Invertible Mathematical Model of Cortical Bone’s Adaptation to Mechanical Loading

“…The periosteal new bone formation is, therefore, more consistent than endocortical new bone formation, as also evident from other works of Srinivasan et al . 48,49 . The current model does not take into account of such differences between the two surfaces.…”

Muscle paralysis induces bone marrow inflammation and predisposition to formation of giant osteoclasts

“…To compare osteoclast size in cultures, a Kolmogorov-Smirnov (KS) test was first used to compare the distribution in cell areas. Next, normalized population distributions (i.e., percentage of cell population at a given area) were determined and fit with separate power law curves using maximum likelihood estimation (MLE) and likelihood ratio testing (LRT) as described previously (46). Finally, we assessed whether the data sets could be fit by a single power law model via MLE and LRT.…”

Enhancement of Flow-Induced AP-1 Gene Expression by Cyclosporin A Requires NFAT-Independent Signaling in Bone Cells

“…46–48 Recent evidence suggests that Cyclosporin A (CsA), a small peptide immunosuppressant that inhibits calcineurin and its substrate Nuclear factor of activated T cells (NFAT), may alter bone signaling pathways that affect bone mass accrual. For example, while one of the observed side effects of extended exposure to CsA and other calcineurin inhibitors has been severe bone loss in both animals and humans, 50 it has also been shown to inhibit osteoclast formation and function, 34 and enhance osteoblast differentiation.…”