Rest-inserted loading rapidly amplifies the response of bone to small increases in strain and load cycles

Srinivasan, Sundar; Ausk, Brandon J.; Poliachik, Sandra L.; Warner, Sarah; Richardson, Thomas S.; Gross, Ted S.

doi:10.1152/japplphysiol.00507.2006

Cited by 80 publications

(103 citation statements)

References 36 publications

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“…Surprisingly, we found that 32 wk old C3H mice were highly responsive to rest-inserted loading, even though this regimen was nearly 50% lower in magnitude than was found to be ineffective in 16 wk old C3H mice. Further, the Ps.BFR/BS induced in 32 wk C3H mice by this rest-inserted regimen exceeded that induced in 16 wk C57 mice by 113.9% (the data in the C57 mice were similar to previous data from our group [43]). This study also demonstrates that optimal timing for the application of mechanical loading to enhance bone formation can vary with the genetic makeup and developmental stage of the individual animal.…”

Section: Discussionsupporting

confidence: 89%

“…As has been previously reported in the literature for cyclic loading [17][18][19]25], our initial study also indicated that 16 wk C3H mice did not respond to a rest-inserted loading protocol that had previously been found to be highly osteogenic in C57 mice [43]. However, at 32 wk of age, when C3H mice demonstrated baseline Ps.BFR/BS within 5% of that of 16 wk old C57 mice (a common age for use in mechanotransduction studies), a rest-inserted loading regimen of much lower amplitude (45% less than the initial study) significantly elevated Ps.BFR/BS in C3H mice.…”

Section: Discussionsupporting

confidence: 83%

“…A C3H mouse was sacrificed every 2 wk following 16 wk of age and dynamic histomorphometry was used to determine Ps.BFR/BS at the tibia middiaphysis. We found that Ps.BFR/BS in C3H mice at 32 wk of age was equivalent to within 5% of that observed in 16 wk C57 mice in our previous studies [43]. C3H mice at 32 wk of age were therefore used in the following studies to examine if the C3H strain was capable of responding to low and moderate magnitude mechanical stimuli without the confounding influence of high basal surface osteoblast activity.…”

Section: Age-matched Studymentioning

confidence: 59%

“…Based upon a previous study reporting cross-sectional areas of 16 wk C3H mice [42], we estimated a priori a loading regimen that would induce peak periosteal normal strains of 2200με. This magnitude of waveform was 40% greater than a restinserted waveform that induced significant periosteal bone formation rate (Ps.BFR) in 16 wk C57 mice [43]. Post-hoc animal specific estimates of induced strains were determined using beam theory (as described in the section on calibration).…”

Section: Age-matched Studymentioning

confidence: 99%

“…Using strain distributions from the validated FE model, we applied beam theory to calculate force and moment boundary conditions for tibia mid-diaphysis loading [43]. Following sacrifice, the boundary conditions were applied to the morphology of the middiaphysis section of the mirrored contralateral left tibia (as used in dynamic histomorphometry, described below) to determine the strain distribution induced at the initiation of the loading experiments for each mouse utilized in the studies.…”

Section: Post-experimental Determination Of Animal Specific Peak Strainsmentioning

confidence: 99%

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32 wk old C3H/HeJ mice actively respond to mechanical loading

Poliachik

Threet

Srinivasan

et al. 2008

Bone

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Numerous studies indicate that C3H/HeJ (C3H) mice are mildly responsive to mechanical loading compared to C57BL/6J (C57) mice. Guided by data indicating high baseline periosteal osteoblast activity in 16 wk C3H mice, we speculated that simply allowing the C3H mice to age until basal periosteal bone formation was equivalent to that of 16 wk C57 mice would restore mechanoresponsiveness in C3H mice. We tested this hypothesis by subjecting the right tibiae of 32 wk old C3H mice and 16 wk old C57 mice to low magnitude rest-inserted loading (peak strain: 1235με) and then exposing the right tibiae of 32 wk C3H mice to low (1085με) or moderate (1875 με) magnitude cyclic loading. The osteoblastic response to loading on the endocortical and periosteal surfaces was evaluated via dynamic histomorphometry. At 32 wk of age, C3H mice responded to low magnitude rest-inserted loading with significantly elevated periosteal mineralizing surface, mineral apposition rate and bone formation compared to unloaded contralateral bones. Surprisingly, the periosteal bone formation induced by low magnitude rest-inserted loading in C3H mice exceeded that induced in 16 wk C57 mice. At 32 wk of age, C3H mice also demonstrated an elevated response to increased magnitudes of cyclic loading. We conclude that a high level of basal osteoblast function in 16 wk C3H mice appears to overwhelm the ability of the tissue to respond to an otherwise anabolic mechanical loading stimulus. However, when basal surface osteoblast activity is equivalent to that of 16 wk C57 mice, C3H mice demonstrate a clear ability to respond to either rest-inserted or cyclic loading.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 83%

Section: Age-matched Studymentioning

confidence: 59%

Section: Age-matched Studymentioning

confidence: 99%

Section: Post-experimental Determination Of Animal Specific Peak Strainsmentioning

confidence: 99%

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32 wk old C3H/HeJ mice actively respond to mechanical loading

Poliachik

Threet

Srinivasan

et al. 2008

Bone

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Static Preload Inhibits Loading‐Induced Bone Formation

et al. 2018

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Nearly all exogenous loading models of bone adaptation apply dynamic loading superimposed upon a time invariant static preload (SPL) in order to ensure stable, reproducible loading of bone. Given that SPL may alter aspects of bone mechanotransduction (eg, interstitial fluid flow), we hypothesized that SPL inhibits bone formation induced by dynamic loading. As a first test of this hypothesis, we utilized a newly developed device that enables stable dynamic loading of the murine tibia with SPLs ≥ −0.01 N. We subjected the right tibias of BALB/c mice (4‐month‐old females) to dynamic loading (−3.8 N, 1 Hz, 50 cycles/day, 10 s rest) superimposed upon one of three SPLs: −1.5 N, −0.5 N, or −0.03 N. Mice underwent exogenous loading 3 days/week for 3 weeks. Metaphyseal trabecular bone adaptation (μCT) and midshaft cortical bone formation (dynamic histomorphometry) were assessed following euthanasia (day 22). Ipsilateral tibias of mice loaded with a −1.5‐N SPL demonstrated significantly less trabecular bone volume/total volume (BV/TV) than contralateral tibias (−12.9%). In contrast, the same dynamic loading superimposed on a −0.03‐N SPL significantly elevated BV/TV versus contralateral tibias (12.3%) and versus the ipsilateral tibias of the other SPL groups (−0.5 N: 46.3%, −1.5 N: 37.2%). At the midshaft, the periosteal bone formation rate (p.BFR) induced when dynamic loading was superimposed on −1.5‐N and −0.5‐N SPLs was significantly amplified in the −0.03‐N SPL group (>200%). These data demonstrate that bone anabolism induced by dynamic loading is markedly inhibited by SPL magnitudes commonly implemented in the literature (ie, −0.5 N, −1.5 N). The inhibitory impact of SPL has not been recognized in bone adaptation models and, as such, SPLs have been neither universally reported nor standardized. Our study therefore identifies a previously unrecognized, potent inhibitor of mechanoresponsiveness that has potentially confounded studies of bone adaptation and translation of insights from our field. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

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Cancellous Bone May Have a Greater Adaptive Strain Threshold Than Cortical Bone

et al. 2021

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Strain magnitude has a controlling influence on bone adaptive response. However, questions remain as to how and if cancellous and cortical bone tissues respond differently to varied strain magnitudes, particularly at a molecular level. The goal of this study was to characterize the time‐dependent gene expression, bone formation, and structural response of the cancellous and cortical bone of female C57Bl/6 mice to mechanical loading by applying varying load levels (low: −3.5 N; medium: −5.2 N; high: −7 N) to the skeleton using a mouse tibia loading model. The loading experiment showed that cortical bone mass at the tibial midshaft was significantly enhanced following all load levels examined and bone formation activities were particularly elevated at the medium and high loads applied. In contrast, for the proximal metaphyseal cancellous bone, only the high load led to significant increases in bone mass and bone formation indices. Similarly, expression of genes associated with inhibition of bone formation (e.g., Sost) was altered in the diaphyseal cortical bone at all load levels, but in the metaphyseal cortico‐cancellous bone only by the high load. Finite element analysis determined that the peak tensile or compressive strains that were osteogenic for the proximal cancellous bone under the high load were significantly greater than those that were osteogenic for the midshaft cortical tissues under the low load. These results suggest that the magnitude of the strain stimulus regulating structural, cellular, and molecular responses of bone to loading may be greater for the cancellous tissues than for the cortical tissues. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Rest-inserted loading rapidly amplifies the response of bone to small increases in strain and load cycles

Cited by 80 publications

References 36 publications

32 wk old C3H/HeJ mice actively respond to mechanical loading

32 wk old C3H/HeJ mice actively respond to mechanical loading

Static Preload Inhibits Loading‐Induced Bone Formation

Cancellous Bone May Have a Greater Adaptive Strain Threshold Than Cortical Bone

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