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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052144-15
Application #
8878173
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Lester, Gayle E
Project Start
2002-09-30
Project End
2019-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
15
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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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 :
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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
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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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