Rationale and Objectives: Immobilization-related bone loss occurs in many neurological conditions including stroke, spinal cord injury (SCI), multiple sclerosis, and amyotrophic lateral sclerosis. The bone loss after an SCI is particularly rapid and severe. The thinning bones of individuals with neurological conditions place them at increased risk for fractures after falls or even from trauma due to minor impacts. Such fractures result in hospitalization, cost, and decreased quality of life. About 46 % of individuals with SCI may have a fracture over their lifetime, a substantially elevated risk. Despite the pressing nature of this problem, to date, the most severe forms of immobilization-related bone loss (e.g., SCI) have been refractory to the FDA-approved medications for osteoporosis tested for this indication. This application aims to address this critical need for therapy. Whole body low intensity vibration (LIV) is receiving a great deal of attention as a potential means to slow or prevent osteoporosis. For example, LIV reduced bone loss in postmenopausal women and children with cerebral palsy. Whether LIV improves bone mass in patients with SCI is not known, although one case report suggests some beneficial effect. We have recently conducted pilot studies to evaluate the effects of LIV on bone loss using a rat model of moderately severe SCI. LIV was initiated at 28 days after SCI and continued for 35 days. LIV induced favorable changes in blood markers of bone formation and gene expression of cultured bone-forming cells. Our pilot results establish for the first time the potential benefits of LIV on the skeleton in an SCI model, and for the first time in a model of severe neurologic disease or disorder. However, LIV did not increase bone mineral density. A recent study demonstrated that whole-body vibration (WBV) partially attenuated bone deterioration during the early stage in rats with motor-complete (severe) SCI. Our initial work and current knowledge have provided solid support for further study of the use of LIV as a convenient therapeutic option for SCI-related bone loss. The premise that underlies this application is that LIV will be more effective if administrated for a prolonged time, and when combined with medicines that reduce net bone loss, specifically one medicine that reduces bone thinning (anti-RANKL antibody) and one that promotes building new bone (androgens) as novel treatments to block bone loss after SCI. Objective 1: In rat models of moderate contusion SCI, we will test whether a prolonged course of LIV will provide be a more pronounced effect in preserving bone. We will also study the mechanisms by which LIV might stimulate bone formation and reduce bone resorption that is involved in the regulation of osteocytes. In addition,,we will evaluate whether an anti-RANKL antibody and/or androgen, when administered in conjunction with LIV, enhance the effects of LIV on sublesional bone loss after SCI Objective 2. In rat models of severe SCI, we will evaluate whether a prolonged course of LIV will protect against bone loss subacutely after severe SCI in non-weight bearing conditions; and whether such effects can be further augmented by the application of anti-RANKL antibody and/or androgen in combination with LIV. Significance and Impact: Results of the research may be applied to slow or reverse bone loss after SCI. It is uncertain as yet whether this benefit will be to delay the onset of severe bone loss, or instead whether bone loss can be blocked completely. In either case, one can envision use of proposed interventions to at least spare bone until neuroreparative treatments become available. In addition, the proposed interventions hold the promise of increasing the number of individuals eligible for weight bearing rehabilitation strategies, such as ReWalk, eLegs, or other modalities for gait training and functional independence. Knowledge regarding molecular mechanisms will be applicable in a more fundamental way, by providing insights into basic mechanisms of mechanic reloading and androgen actions. Lastly, findings may be applicable by providing insight for future related basic science studies, or directing the development of future pharmaceuticals.
There are more than 40,000 Veterans living with SCI in the United States. Knowledge gained through our studies holds the potential to develop novel treatments (LIV alone and/or in combination with anti-RANKL antibody and androgens) for bone loss after an extensive period of time following SCI, and, thus improve quality of life and function of Veterans suffering from SCI. Information from these studies should be readily transferrable to address bone loss in other neurological conditions including stroke, muscular dystrophy, and amyelotrophic lateral sclerosis. Knowledge regarding molecular mechanisms will be applicable in a more fundamental way, by providing insights into basic mechanisms of mechanic reloading and androgen actions. Mechanistic insights from the proposed study may further improve efforts to prevent SCI-related deterioration of bone.
| Qin, Yiwen; Peng, Yuanzhen; Zhao, Wei et al. (2017) Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: A novel mechanism in muscle-bone communication. J Biol Chem 292:11021-11033 |
