Acute and Delayed Systemic Treatment with Cannabinoid Receptor 2 Agonists to Prevent or Treat/Reverse Osteoporosis in a Mouse Model of SCI
Abstract
Spinal cord injury (SCI) produces what is generally a permanent loss of both neurosensory and motor function. As there are no currently effective treatments to preserve or restore function, individuals who have received an SCI face a lifetime of deficits that negatively impact overall quality of life. One such deficit is the development of osteoporosis or loss of bone density. Osteoporosis, occurring under conditions of aging and/or menopause, can evolve over years to decades in individuals. However, loss of bone density, particularly in bones below the spinal level of injury, can be both rapid and dramatic in the initial weeks to months following SCI. Such bone loss significantly increases the risk of bone fracture in the aging and post-menopausal communities. A similar risk occurs in the SCI community, but here the risks can be life-threatening as often the loss of neural input below the spinal level of injury leaves the area insensate. As a result, the patient may be unaware of the fracture, leading to the risk of significantly greater tissue damage. Current treatments for SCI-induced osteoporosis are less than optimal and include physical rehabilitation and/or the use of bisphosphonate drugs to enhance bone mineralization. Paradoxically, however, the long-term use of bisphosphonates in the treatment of SCI-induced osteoporosis has led to reports of even greater demineralization. Clearly, newer, more effective treatments to preserve bone integrity are needed to improve the overall quality of life for those living with an SCI. Cannabinoid drugs, specifically those that work via stimulation of the cannabinoid-2 (CB2) receptor, have been shown to regulate bone growth dynamics during development by encouraging bone growth over resorption. CB2 agonists such as HU-308 have been shown to reduce or delay the onset of bone loss in mouse models of osteoporosis. Of even greater interest, delayed treatment with HU-308 was suggested to reverse osteoporosis in a mouse menopause model in which treatment was delayed until after osteoporosis was already established. While it remains unclear how SCI-induced osteoporosis differs from age- and/or menopausal-dependent bone loss, we wish to determine whether the CB2 agonist HU-308 can be developed in a preclinical mouse model of SCI as a novel therapeutic to either prevent or reverse osteoporosis. We will first determine whether early, but sustained treatment with HU-308 can prevent the onset of osteoporosis when initiated by 3 hours post-injury and continued daily. Hind limb bone density will be measured after 40 days of treatment by micro-CT X-ray and end-stage histological measures. Secondly, we will address the question of whether delayed treatment with HU-308 can reverse osteoporosis that develops during the chronic phase of SCI. Using the same mouse model of injury, osteoporosis will be allowed to develop over a 3-month period before treatment is initiated. If our hypothesis is correct and we observe a reversal in established osteoporosis, it would represent a significant advancement in the long-term treatment of SCI patients. The ability to reverse osteoporosis would reduce long-term risk of fracture and dramatically enhance patient overall quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610349
Entities
People
- Raymond Grill
Organizations
- United States Army
- University of Mississippi