BackgroundBone structure and strength are rapidly lost during conditions of decreased mechanical loading, and aged bones have a diminished ability to adapt to increased mechanical loading. This is a concern for older patients that experience periods of limited mobility or bed rest, but the acute effects of disuse on the bones of aged patients have not been thoroughly described. Previous animal studies have primarily examined the effect of mechanical unloading on young animals. Those that have studied aged animals have exclusively focused on bone loss during unloading and not bone recovery during subsequent reloading. In this study, we investigated the effect of decreased mechanical loading and subsequent reloading on bone using a hindlimb unloading model in Adult (9 month old) and Aged (28 month old) male rats.MethodsAnimals from both age groups were subjected to 14 days of hindlimb unloading followed by up to 7 days of reloading. Additional Aged rats were subjected to 7 days of forced treadmill exercise during reloading or a total of 28 days of reloading. Trabecular and cortical bone structure of the femur were quantified using ex vivo micro-computed tomography (μCT), and mechanical properties were quantified with mechanical testing.ResultsWe found that Adult rats had substantially decreased trabecular bone volume fraction (BV/TV) following unloading (− 27%) while Aged animals did not exhibit significant bone loss following unloading. However, Aged animals had lower trabecular BV/TV after 3 days of reloading (− 20% compared to baseline), while trabecular BV/TV of Adult rats was not different from baseline values after 3 days of reloading. Trabecular BV/TV of Aged animals remained lower than control animals even with exercise during 7 days of reloading and after 28 days of reloading.ConclusionsThese data suggest that aged bone is less responsive to both increased and decreased mechanical loading, and that acute periods of disuse may leave older subjects with a long-term deficit in trabecular bone mass. These finding indicate the need for therapeutic strategies to improve the skeletal health of elderly patients during periods of disuse.
Osteophytes are a typical radiographic finding during osteoarthritis (OA), but the mechanisms leading to their formation are not well known. Comparatively, fracture calluses have been studied extensively; therefore, drawing comparisons between osteophytes and fracture calluses may lead to a deeper understanding of osteophyte formation. In this study, we compared the time courses of osteophyte and fracture callus formation, and investigated mechanisms contributing to development of these structure. Additionally, we investigated the effect of mechanical unloading on the formation of both fracture calluses and osteophytes. Mice underwent either transverse femoral fracture or non-invasive anterior cruciate ligament rupture. Fracture callus and osteophyte size and ossification were evaluated after 3, 5, 7, 14, 21, or 28 days. Additional mice were subjected to hindlimb unloading after injury for 3, 7, or 14 days. Protease activity and gene expression profiles after injury were evaluated after 3 or 7 days of normal ambulation or hindlimb unloading using in vivo fluorescence reflectance imaging (FRI) and quantitative PCR. We found that fracture callus and osteophyte growth achieved similar developmental milestones, but fracture calluses formed and ossified at earlier time points. Hindlimb unloading ultimately led to a threefold decrease in chondro/osteophyte area, and a twofold decrease in fracture callus area. Unloading was also associated with decreased inflammation and protease activity in injured limbs detected with FRI, particularly following ACL rupture. qPCR analysis revealed disparate cellular responses in fractured femurs and injured joints, suggesting that fracture calluses and osteophytes may form via different inflammatory, anabolic, and catabolic pathways. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:699-710, 2018.
Our previous studies used tibial compression overload to induce anterior cruciate ligament (ACL) rupture in mice, while others have applied similar or greater compressive magnitudes without injury. The causes of these differences in injury threshold are not known. In this study, we compared knee injury thresholds using a "prone configuration" and a "supine configuration" that differed with respect to hip, knee, and ankle flexion, and utilized different fixtures to stabilize the knee. Right limbs of female and male C57BL/6 mice were loaded using the prone configuration, while left limbs were loaded using the supine configuration. Mice underwent progressive loading from 2 to 20 N, or cyclic loading at 9 N or 14 N (n = 9-11/sex/loading method). Progressive loading with the prone configuration resulted in ACL rupture at an average of 10.2 ± 0.9 N for females and 11.4 ± 0.7 N for males. In contrast, progressive loading with the supine configuration resulted in ACL rupture in only 36% of female mice and 50% of male mice. Cyclic loading with the prone configuration resulted in ACL rupture after 15 ± 8 cycles for females and 24 ± 27 cycles for males at 9 N, and always during the first cycle for both sexes at 14 N. In contrast, cyclic loading with the supine configuration was able to complete 1,200 cycles at 9 N without injury for both sexes, and an average of 45 ± 41 cycles for females and 49 ± 25 cycles for males at 14 N before ACL rupture. These results show that tibial compression configurations can strongly affect knee injury thresholds during loading.
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