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Tibial loading increases osteogenic gene expression and cortical bone volume in mature and middle-aged mice.

ABSTRACT: There are conflicting data on whether age reduces the response of the skeleton to mechanical stimuli. We examined this question in female BALB/c mice of different ages, ranging from young to middle-aged (2, 4, 7, 12 months). We first assessed markers of bone turnover in control (non-loaded) mice. Serum osteocalcin and CTX declined significantly from 2 to 4 months (p<0.001). There were similar age-related declines in tibial mRNA expression of osteoblast- and osteoclast-related genes, most notably in late osteoblast/matrix genes. For example, Col1a1 expression declined 90% from 2 to 7 months (p<0.001). We then assessed tibial responses to mechanical loading using age-specific forces to produce similar peak strains (-1300 µε endocortical; -2350 µε periosteal). Axial tibial compression was applied to the right leg for 60 cycles/day on alternate days for 1 or 6 weeks. qPCR after 1 week revealed no effect of loading in young (2-month) mice, but significant increases in osteoblast/matrix genes in older mice. For example, in 12-month old mice Col1a1 was increased 6-fold in loaded tibias vs. controls (p = 0.001). In vivo microCT after 6 weeks revealed that loaded tibias in each age group had greater cortical bone volume (BV) than contralateral control tibias (p<0.05), due to relative periosteal expansion. The loading-induced increase in cortical BV was greatest in 4-month old mice (+13%; p<0.05 vs. other ages). In summary, non-loaded female BALB/c mice exhibit an age-related decline in measures related to bone formation. Yet when subjected to tibial compression, mice from 2-12 months have an increase in cortical bone volume. Older mice respond with an upregulation of osteoblast/matrix genes, which increase to levels comparable to young mice. We conclude that mechanical loading of the tibia is anabolic for cortical bone in young and middle-aged female BALB/c mice.

SUBMITTER: Silva MJ

PROVIDER: S-EPMC3325918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Classic studies in bone mechanobiology have established the importance of loading parameters on the anabolic response. Most of these early studies were done using loading methods not currently in favor, and using non-murine species. Our objective was to re-examine the effects of several loading parameters on the response of cortical bone using the contemporary murine axial tibial compression model. We subjected tibias of 5-month old, female C57Bl/6 mice to cyclic (4?Hz) mechanical loading and examined bone formation responses using dynamic and static histomorphometry. First, using a reference protocol of 1,200 cycles/day, 5 days/week for 2 weeks, we confirmed the significant influence of peak strain magnitude on periosteal mineralizing surface (Ps.MS/BS) and bone formation rate (Ps.BFR/BS) (p?<?0.05, ANOVA). There was a significant induction of periosteal lamellar bone at a lower threshold of approx. -1,000??? and a transition from lamellar-woven bone near -2,000???. In contrast, on the endocortical surface, bone formation indices did not exhibit a load magnitude-dependent response and no incidence of woven bone. Next, we found that reducing daily cycle number from 1,200 to 300 to 60 did not diminish the bone formation response (p?>?0.05). On the other hand, reducing the daily frequency of loading from 5 consecutive days/week to 3 alternate days/week significantly diminished the periosteal response, from a loading-induced increase in Ps.MS/BS of 38% (loaded vs. control) for 5 days/week to only 15% for 3 days/week (p?<?0.05). Finally, we determined that reducing the study duration from 2 to 1 weeks of loading did not affect bone formation outcomes. In conclusion, cyclic loading to -1,800??? peak strain, at 4?Hz and 60 cycles/day for 5 consecutive days (1 week) induces an increase in periosteal lamellar bone formation with minimal incidence of woven bone in 5-month-old C57Bl/6 female mice. Our results provide a basis for reduction of loading duration (daily cycles and study length) without loss of anabolic effect as measured by dynamic histomorphometry. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:682-691, 2018.

Project description:Bone is a unique living tissue, which responds to the mechanical stimuli regularly imposed on it. Adolescence facilitates a favorable condition for the skeleton that enables the exercise to positively influence bone architecture and overall strength. However, it is still dubious for how long the skeletal benefits gained in adolescence is preserved at adulthood. The current study aims to use a rat model to investigate the effects of in vivo low- (LI), medium- (MI), and high- (HI) intensity cyclic loadings applied during puberty on longitudinal bone development, morphometry, and biomechanics during adolescence as well as at adulthood. Forty-two young (4-week-old) male rats were randomized into control, sham, LI, MI, and HI groups. After a 5 day/week for 8 weeks cyclic loading regime applied on the right tibia, loaded rats underwent a subsequent 41-week, normal cage activity period. Right tibias were removed at 52 weeks of age, and a comprehensive assessment was performed using μCT, mechanical testing, and finite element analysis. HI and MI groups exhibited reduced body weight and food intake at the end of the loading period compared with shams, but these effects disappeared afterward. HI cyclic loading increased BMD, bone volume fraction, trabecular thickness, trabecular number, and decreased trabecular spacing after loading. All loading-induced benefits, except BMD, persisted until the end of the normal cage activity period. Moreover, HI loading induced enhanced bone area, periosteal perimeter, and moment of inertia, which remained up to the 52nd week. After the normal cage activity at adulthood, the HI group showed increased ultimate force and stress, stiffness, postyield displacement and energy, and toughness compared with the sham group. Overall, our findings suggest that even though both trabecular and cortical bone drifted through age-related changes during aging, HI cyclic loading performed during adolescence can render lifelong benefits in bone microstructure and biomechanics. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Tibial loading increases osteogenic gene expression and cortical bone volume in mature and middle-aged mice.

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