scholarly journals The Skeletal Cellular and Molecular Underpinning of the Murine Hindlimb Unloading Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Priyanka Garg ◽  
Maura Strigini ◽  
Laura Peurière ◽  
Laurence Vico ◽  
Donata Iandolo
Keyword(s):  
Bone Loss ◽  
Mechanical Loading ◽  
Weight Bearing ◽  
Bone Adaptation ◽  
Hindlimb Unloading ◽  
Molecular Pathways ◽  
Long Bones ◽  
Confounding Factors ◽  
Environmental Temperatures

Bone adaptation to spaceflight results in bone loss at weight bearing sites following the absence of the stimulus represented by ground force. The rodent hindlimb unloading model was designed to mimic the loss of mechanical loading experienced by astronauts in spaceflight to better understand the mechanisms causing this disuse-induced bone loss. The model has also been largely adopted to study disuse osteopenia and therefore to test drugs for its treatment. Loss of trabecular and cortical bone is observed in long bones of hindlimbs in tail-suspended rodents. Over the years, osteocytes have been shown to play a key role in sensing mechanical stress/stimulus via the ECM-integrin-cytoskeletal axis and to respond to it by regulating different cytokines such as SOST and RANKL. Colder experimental environments (~20–22°C) below thermoneutral temperatures (~28–32°C) exacerbate bone loss. Hence, it is important to consider the role of environmental temperatures on the experimental outcomes. We provide insights into the cellular and molecular pathways that have been shown to play a role in the hindlimb unloading and recommendations to minimize the effects of conditions that we refer to as confounding factors.

scholarly journals Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lei Qin ◽  
Xuekun Fu ◽  
Jing Ma ◽  
Manxia Lin ◽  
Peijun Zhang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Mechanical Stimulation ◽  
Fluid Shear Stress ◽  
Weight Bearing ◽  
Underlying Mechanism ◽  
Long Bones ◽  
Cell Orientation ◽  
Cytoskeleton Organization

AbstractOsteocytes act as mechanosensors in bone; however, the underlying mechanism remains poorly understood. Here we report that deleting Kindlin-2 in osteocytes causes severe osteopenia and mechanical property defects in weight-bearing long bones, but not in non-weight-bearing calvariae. Kindlin-2 loss in osteocytes impairs skeletal responses to mechanical stimulation in long bones. Control and cKO mice display similar bone loss induced by unloading. However, unlike control mice, cKO mice fail to restore lost bone after reloading. Osteocyte Kindlin-2 deletion impairs focal adhesion (FA) formation, cytoskeleton organization and cell orientation in vitro and in bone. Fluid shear stress dose-dependently increases Kindlin-2 expression and decreases that of Sclerostin by downregulating Smad2/3 in osteocytes; this latter response is abolished by Kindlin-2 ablation. Kindlin-2-deficient osteocytes express abundant Sclerostin, contributing to bone loss in cKO mice. Collectively, we demonstrate an indispensable novel role of Kindlin-2 in maintaining skeletal responses to mechanical stimulation by inhibiting Sclerostin expression during osteocyte mechanotransduction.

scholarly journals Mechanotransduction in Musculoskeletal Tissue Regeneration: Effects of Fluid Flow, Loading, and Cellular-Molecular Pathways

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Yi-Xian Qin ◽  
Minyi Hu
Keyword(s):  
Fluid Flow ◽  
Bone Loss ◽  
Mechanical Loading ◽  
Tissue Regeneration ◽  
Underlying Mechanism ◽  
Bone Adaptation ◽  
Bone Tissue Regeneration ◽  
Molecular Pathways ◽  
Musculoskeletal Tissue ◽  
Mechanical Signals

While mechanotransductive signal is proven essential for tissue regeneration, it is critical to determine specific cellular responses to such mechanical signals and the underlying mechanism. Dynamic fluid flow induced by mechanical loading has been shown to have the potential to regulate bone adaptation and mitigate bone loss. Mechanotransduction pathways are of great interests in elucidating how mechanical signals produce such observed effects, including reduced bone loss, increased bone formation, and osteogenic cell differentiation. The objective of this review is to develop a molecular understanding of the mechanotransduction processes in tissue regeneration, which may provide new insights into bone physiology. We discussed the potential for mechanical loading to induce dynamic bone fluid flow, regulation of bone adaptation, and optimization of stimulation parameters in various loading regimens. The potential for mechanical loading to regulate microcirculation is also discussed. Particularly, attention is allotted to the potential cellular and molecular pathways in response to loading, including osteocytes associated with Wnt signaling, elevation of marrow stem cells, and suppression of adipotic cells, as well as the roles of LRP5 and microRNA. These data and discussions highlight the complex yet highly coordinated process of mechanotransduction in bone tissue regeneration.

scholarly journals Simulated spaceflight produces a rapid and sustained loss of osteoprogenitors and an acute but transitory rise of osteoclast precursors in two genetic strains of mice

2012 ◽  
Vol 303 (11) ◽  
pp. E1354-E1362 ◽  
Author(s):  
Mohammad Shahnazari ◽  
Pam Kurimoto ◽  
Benjamin M. Boudignon ◽  
Benjamin E. Orwoll ◽  
Daniel D. Bikle ◽  
...  
Keyword(s):  
Bone Loss ◽  
Cancellous Bone ◽  
Bone Structure ◽  
Bone Cells ◽  
Weight Bearing ◽  
Bone Adaptation ◽  
Hindlimb Unloading ◽  
Skeletal Unloading ◽  
Precursor Pool ◽  
Cancellous Bone Structure

Loss of skeletal weight bearing or skeletal unloading as occurs during spaceflight inhibits bone formation and stimulates bone resorption. These are associated with a decline in the osteoblast (Ob.S/BS) and an increase in the osteoclast (Oc.S/BS) bone surfaces. To determine the temporal relationship between changes in the bone cells and their marrow precursor pools during sustained unloading, and whether genetic background influences these relationships, we used the hindlimb unloading model to induce bone loss in two strains of mice known to respond to load and having significantly different cancellous bone volumes (C57BL/6 and DBA/2 male mice). Skeletal unloading caused a progressive decline in bone volume that was accompanied by strain-specific changes in Ob.S/BS and Oc.S/BS. These were associated with a sustained reduction in the osteoprogenitor population and a dramatic but transient increase in the osteoclast precursor pool size in both strains. The results reveal that bone adaptation to skeletal unloading involves similar rapid changes in the osteoblast and osteoclast progenitor populations in both strains of mice but striking differences in Oc.S/BS dynamics, BFR, and cancellous bone structure. These strain-specific differences suggest that genetics plays an important role in determining the osteoblast and osteoclast populations on the bone surface and the dynamics of bone loss in response to skeletal unloading.

scholarly journals The role of Tai Chi Chuan exercise on osteoporosis prevention and treatment in postmenopausal women

2011 ◽  
Vol 1 (1) ◽  
pp. 10
Author(s):  
Haiyan Chen
Keyword(s):  
Bone Loss ◽  
Postmenopausal Women ◽  
Tai Chi ◽  
Weight Bearing ◽  
Depression And Anxiety ◽  
Osteoporosis Prevention ◽  
Mineral Density ◽  
Cross Sectional ◽  
Tai Chi Chuan

Osteoporosis is a disease characterized by fragile bones and high susceptibility to low trauma fractures. Tai Chi, an ancient Chinese mind-body exercise that is reported to enhance muscle function, balance and flexibility, and to reduce pain, depression and anxiety, may safely and effectively be used to prevent or treat osteoporosis. The aim of this review is to evaluate the evidence for Tai Chi as an intervention to reduce rate of bone loss in postmenopausal women. A literature search on randomized controlled trials (RCTs), prospective cohort studies, and cross-sectional studies that included Tai Chi as an intervention, and had at least 1 outcome related to measurement of bone metabolism were identified in PubMed/Medline. Twenty-one controlled studies were identified in the database, which suggested Tai Chi slowed down the loss of bone mineral density in most postmenopausal women, improved balance and strength, relieves pain from arthritis, and improved mental strength so they can cope better with chronic diseases. Regular Tai Chi Chuan exercise is beneficial for retarding bone loss in the weight-bearing bones of postmenopausal women.

Mechanisms of bone remodeling during weight-bearing exercise

2006 ◽  
Vol 31 (6) ◽  
pp. 655-660 ◽  
Author(s):  
Ronald Zernicke ◽  
Christopher MacKay ◽  
Caeley Lorincz
Keyword(s):  
Mechanical Loading ◽  
Bone Structure ◽  
Weight Bearing ◽  
Bone Cell ◽  
Bone Adaptation ◽  
Bone Modeling ◽  
Extrinsic Factors ◽  
Paracrine Factors ◽  
Loading Effects ◽  
Exercise Induced

Exercise-induced mechanical loading can have potent effects on skeletal form and health. Both intrinsic and extrinsic factors contribute to bone structure and function. Mechanical simuli (e.g., strain magnitude, frequency, rate, and gradients, as well as fluid flow and shear stress) have potent influences on bone-cell cytoskeleton and associated signalling pathways. Although the immature skeleton may be more able to benefit from exercise, a skeletally mature population can also benefit from exercise programs aimed at increasing the functional loads to which the skeleton is exposed. The definitive explanation of mechanical-loading and (or) bone-cell mechanotransductive phenomena, however, remains elusive. Here, we briefly review the structural and anatomical foundation for bone adaptation, focusing on mechanical loading effects on bone, linked to the roles of integrins, cytoskeleton, membrane channels, and auto- and paracrine factors in bone modeling and remodeling.

scholarly journals Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Cori N. Booker ◽  
Christopher L. Haga ◽  
Siddaraju V. Boregowda ◽  
Jacqueline Strivelli ◽  
Donald G. Phinney
Keyword(s):  
Bone Loss ◽  
Progenitor Cells ◽  
Structural Changes ◽  
Weight Bearing ◽  
Hindlimb Unloading ◽  
Integrative Approach ◽  
Transcriptional Responses ◽  
Time Resolved ◽  
Mechanical Unloading ◽  
Transcript Profiles

AbstractDisuse osteoporosis (DO) results from mechanical unloading of weight-bearing bones and causes structural changes that compromise skeletal integrity, leading to increased fracture risk. Although bone loss in DO results from imbalances in osteoblast vs. osteoclast activity, its effects on skeletal stem/progenitor cells (SSCs) is indeterminate. We modeled DO in mice by 8 and 14 weeks of hindlimb unloading (HU) or 8 weeks of unloading followed by 8 weeks of recovery (HUR) and monitored impacts on animal physiology and behavior, metabolism, marrow adipose tissue (MAT) volume, bone density and micro-architecture, and bone marrow (BM) leptin and tyrosine hydroxylase (TH) protein expression, and correlated multi-systems impacts of HU and HUR with the transcript profiles of Lin−LEPR+ SSCs and mesenchymal stem cells (MSCs) purified from BM. Using this integrative approach, we demonstrate that prolonged HU induces muscle atrophy, progressive bone loss, and MAT accumulation that paralleled increases in BM but not systemic leptin levels, which remained low in lipodystrophic HU mice. HU also induced SSC quiescence and downregulated bone anabolic and neurogenic pathways, which paralleled increases in BM TH expression, but had minimal impacts on MSCs, indicating a lack of HU memory in culture-expanded populations. Although most impacts of HU were reversed by HUR, trabecular micro-architecture remained compromised and time-resolved changes in the SSC transcriptome identified various signaling pathways implicated in bone formation that were unresponsive to HUR. These findings indicate that HU-induced alterations to the SSC transcriptome that persist after reloading may contribute to poor bone recovery.

Daily Acute Bouts of Weight-bearing During Hindlimb Unloading Mitigate Disuse-Induced Deficits in Cancellous Bone

2020 ◽  
Vol 6 (2) ◽  
pp. 2-11 ◽  
Author(s):  
Rihana S. Bokhari ◽  
Corinne E. Metzger ◽  
Matthew R. Allen ◽  
Susan A. Bloomfield
Keyword(s):  
Bone Loss ◽  
Cancellous Bone ◽  
Weight Bearing ◽  
Space Station ◽  
Hindlimb Unloading ◽  
Mineral Density ◽  
Normal Loading ◽  
Bone Mineral Density Loss ◽  
Total Body Mass ◽  
Total Body

AbstractInternational Space Station crewmembers experience microgravity, resulting in musculoskeletal losses. It remains unclear how much mechanical loading during disuse is sufficient to mitigate disuse-induced bone loss. We examined 75 minutes of weight-bearing per day on disuse-induced bone loss during hindlimb unloading (HU). Female C57BL/6J mice, 17 weeks (n=10/group), were exposed to HU for 28 days or were ambulatory controls (CC). Half of the HU animals were continuously unloaded while the remainder were removed from tail suspension for ~75 min/day for cage activity weight-bearing (HU+WB). HU and HU+WB led to total body mass and bone mineral density loss. HU+WB mitigated HU-induced losses in total body fat and lean mass and, in the distal femur, prevented losses in μCT measures of cancellous bone volume and microarchitecture. These findings support the robust impact of short durations of normal loading on preventing or mitigating HU-induced bone loss.

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