The long-term objective of this study is to elucidate the mechanisms underlying loading-induced bone remodeling and develop unique loading-based therapies for preventing bone loss. The specific goal of this study, based on our most recent observations, is to determine how mechanical loading to the knee (knee loading - application of mild lateral loads to the knee) may exert global suppression of osteoclast development not only in the loaded (on-site) bone but also in the non-loaded (remote) bone. As a potential regulatory mechanism, we will focus on secretory factors (e.g., Wnt3a, NGF?, TNF?, etc.) and low-density lipoprotein receptor-related protein 5 (Lrp5) mediated signaling. In the parent project, we have shown that knee loading enhances bone formation in the tibia and the femur through the oscillatory modulation of intramedullary pressure. However, its effects on bone resorption have not been well understood. Preliminary studies using a mouse ovariectomized model, which mimics post-menopausal osteoporosis, indicate that knee loading can suppress development of multi-nucleated osteoclasts from bone marrow cells, and the loading effects are observed not only in the loaded femur but also in the non-loaded contralateral femur. In this competitive renewal project, we will test the hypothesis that joint loading (knee/elbow loading) can suppress an OVX-induced osteoclastogenesis in a systemic manner through Lrp5-mediated Wnt signaling with Wnt3a as a secretory factor, as well as interactions with other secretory factors. To examine this hypothesis, we propose two specific aims using a mouse loading model (knee loading, elbow loading, ulna bending, and tibia loading), and assays for bone remodeling and primary bone marrow cells.
Aim 1 : Determine the local and global effects of joint loading on osteoclastogenesis Aim 2: Evaluate the role of load-modulated secretory factors in osteoclastogenesis In response to mechanical loading, we will conduct X-ray imaging and colony forming unit assays. We will also examine expression of critical secretory factors such as Wnt3a, NGF?, TNF?, OPG, RANKL, etc. in the serum. Primary bone marrow cells will be cultured, and the mechanisms underlying loading-driven regulation of osteoclastogenesis will be investigated. We will examine expression of regulatory factors, including NFATc1 (master transcription factor for osteoclastogenesis) and osteoclast markers such as OSCAR, cathepsin K, etc. We will employ Lrp5 KO mice (global, and conditionally selective to osteocytes), as well as neutralizing antibodies and RNA interference (loss of a function), and plasmids (gain of a function). We expect that this project will contribute to our basic understanding of load-driven regulation of bone resorption and development of loading regimens useful for global prevention of bone loss.

Public Health Relevance

This R01 project will evaluate the effects of mechanical loading on bone remodeling. A specific goal is the evaluation of remote loading effects on osteoclastogenesis. We expect that the results will be useful to develop a unique loading regimen that provides systemic loading effects for treatment of osteoporosis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
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Lester, Gayle E
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Indiana University-Purdue University at Indianapolis
Biomedical Engineering
Biomed Engr/Col Engr/Engr Sta
United States
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Liu, Shengzhi; Fan, Yao; Chen, Andy et al. (2018) Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells. Cancer Res 78:3865-3876
Jiang, Feifei; Liu, Shengzhi; Chen, Andy et al. (2018) Finite Element Analysis of the Mouse Distal Femur with Tumor Burden in Response to Knee Loading. Int J Orthop (Hong Kong) 5:863-871
Jiang, Feifei; Jalali, Aydin; Deguchi, Chie et al. (2018) Finite-element analysis of the mouse proximal ulna in response to elbow loading. J Bone Miner Metab :
Chen, Andy; Wang, Luqi; Liu, Shengzhi et al. (2018) Attraction and Compaction of Migratory Breast Cancer Cells by Bone Matrix Proteins through Tumor-Osteocyte Interactions. Sci Rep 8:5420
Tan, Nian; Li, Xinle; Zhai, Lidong et al. (2018) Effects of knee loading on obesity-related non-alcoholic fatty liver disease in an ovariectomized mouse model with high-fat diet. Hepatol Res 48:839-849
Korupolu, Sandeep; Chien, Stanley; Yokota, Hiroki et al. (2017) Development of an Artificial Finger-Like Knee Loading Device to Promote Bone Health. J Biomed Sci Eng 10:550-561
Li, Xinle; Yang, Jing; Liu, Daquan et al. (2016) Knee loading inhibits osteoclast lineage in a mouse model of osteoarthritis. Sci Rep 6:24668
Liu, Daquan; Li, Xinle; Li, Jie et al. (2015) Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing. Bone 81:620-631
Macione, James; Long, Daniel; Nesbitt, Sterling et al. (2015) Stimulation of osteoblast differentiation with guided ultrasound waves. J Ther Ultrasound 3:12
Hamamura, Kazunori; Chen, Andy; Yokota, Hiroki (2015) Enhancement of osteoblastogenesis and suppression of osteoclastogenesis by inhibition of de-phosphorylation of eukaryotic translation initiation factor 2 alpha. Receptors Clin Investig 2:

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