Differential changes in bone strength of two inbred mouse strains following administration of a sclerostin-neutralizing antibody during growth
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Noah J Mathis1, Emily N Adaniya2, Lauren M Smith3
1School of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Abstract:
Administration of sclerostin-neutralizing antibody (Scl-Ab) treatment has been shown to elicit an anabolic bone response in growing and adult mice. Prior work characterized the response of individual mouse strains but did not establish whether the impact of Scl-Ab on whole bone strength would vary across different inbred mouse strains. Herein, we tested the hypothesis that two inbred mouse strains (A/J and C57BL/6J (B6)) will show different whole bone strength outcomes following sclerostin-neutralizing antibody (Scl-Ab) treatment during growth (4.5-8.5 weeks of age). Treated B6 femurs showed a significantly greater stiffness (S) (68.8% vs. 46.0%) and maximum load (ML) (84.7% vs. 44.8%) compared to A/J. Although treated A/J and B6 femurs showed greater cortical area (Ct.Ar) similarly relative to their controls (37.7% in A/J and 41.1% in B6), the location of new bone deposition responsible for the greater mass differed between strains and may explain the greater whole bone strength observed in treated B6 mice. A/J femurs showed periosteal expansion and endocortical infilling, while B6 femurs showed periosteal expansion. Post-yield displacement (PYD) was smaller in treated A/J femurs (-61.2%, p < 0.001) resulting in greater brittleness compared to controls; an effect not present in B6 mice. Inter-strain differences in S, ML, and PYD led to divergent changes in work-to-fracture (Work). Work was 27.2% (p = 0.366) lower in treated A/J mice and 66.2% (p < 0.001) greater in treated B6 mice relative to controls. Our data confirmed the anabolic response to Scl-Ab shown by others, and provided evidence suggesting the mechanical benefits of Scl-Ab administration may be modulated by genetic background, with intrinsic growth patterns of these mice guiding the location of new bone deposition. Whether these differential outcomes will persist in adult and elderly mice remains to be determined.
Insights
Sclerostin-neutralizing antibody (Scl-Ab) treatment enhances bone strength, but the benefits differ between mouse strains. Genetic background influences how Scl-Ab treatment affects bone growth and mechanical properties, impacting outcomes like stiffness and fracture resistance.
Area of Science:
- Bone Biology and Biomechanics
- Pharmacological Interventions for Skeletal Health
- Genetics and Skeletal Development
Background:
- Sclerostin-neutralizing antibody (Scl-Ab) treatment is known to stimulate bone anabolism.
- Previous studies have not comprehensively evaluated strain-specific responses to Scl-Ab.
- Understanding genetic influences on Scl-Ab efficacy is crucial for potential therapeutic applications.
Purpose of the Study:
- To test if two inbred mouse strains (A/J and C57BL/6J) exhibit different whole bone strength outcomes after Scl-Ab treatment during growth.
- To investigate the impact of genetic background on the anabolic response and mechanical properties of bone following Scl-Ab administration.
Main Methods:
- Scl-Ab was administered to growing mice (4.5-8.5 weeks of age) of A/J and C57BL/6J strains.
- Whole bone strength was assessed using mechanical testing (stiffness, maximum load, post-yield displacement).
- Bone structural parameters, including cortical area and new bone deposition patterns, were analyzed.
Main Results:
- Treated C57BL/6J femurs showed significantly greater stiffness and maximum load compared to A/J.
- Both strains exhibited increased cortical area, but new bone deposition patterns differed (periosteal expansion in both, endocortical infilling in A/J).
- A/J femurs displayed increased brittleness (smaller post-yield displacement), while C57BL/6J did not, leading to divergent changes in work-to-fracture.
Conclusions:
- The anabolic response to Scl-Ab is confirmed, but its mechanical benefits are modulated by genetic background.
- Intrinsic growth patterns of different mouse strains influence the location of new bone formation, affecting overall bone strength.
- Differential outcomes suggest that genetic factors play a significant role in determining the efficacy of Scl-Ab therapy.
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