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Systemic Treatment with Cannabinoid Receptor 2 Agonist to Treat Osteoporosis in a Rodent Model of SCI
Author(s) -
Grayson Bernadette E.,
Pride Yilianys,
Sereduck Susan,
Chade Alejandro,
Grill Raymond,
Tucci Michelle
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02257
Subject(s) - osteoporosis , medicine , bone mineral , bone density , bone remodeling , agonist , spinal cord injury , bone disease , endocrinology , bone fracture , cannabinoid receptor , receptor , spinal cord , radiology , psychiatry
Osteoporosis is a skeletal disease resulting in a reduction of bone mineral density and bone mass with disorganization of trabecular bone architecture, leading to an increased incidence of bone fracture. Nearly all spinal cord injury (SCI) persons will develop osteoporosis following injury, and further up to 50% of all persons with SCI will sustain a fracture during their lives. The mechanism driving osteoporosis following SCI is elusive. The cannabinoid system modulation of bone metabolism through CB1/2 has been increasingly of interest for the preservation of bone mass and density in models of osteoporosis. Here we used early and sustained treatment with selective cannabinoid 2 receptor (CB2) agonist, HU‐308, in a mouse model of SCI to prevent and reverse SCI‐induced osteoporosis. First, we determined the efficacy of acute treatment with CB2 agonist, HU‐308, to stave off osteoporosis with treatment for 40 days post‐injury. In thoracic‐complete transected mice, the bone density was significantly reduced in comparison to injury‐naïve mice. In the distal tibia, HU‐308 was effective to preserve trabecular bone density as measured by Micro‐CT in comparison to SCI mice treated with vehicle (VEH) (P < 0.05) but less so in the proximal tibia. In the femur, 40 days post‐injury, there was no efficacy of HU‐308 to preserve bone density in SCI‐HU‐308 treated mice in comparison to VEH‐treated SCI. Histologic inspection supports substantial loss of trabecular bone. In order to determine if HU‐308 could reverse bone loss, we treated SCI mice with HU‐308, CB2‐agonist significantly after the onset of SCI‐induced osteoporosis (i.e., 3 months post‐injury) for 40 days; this resulted in profoundly improved bone mineral density in SCI mice treated with HU‐308 in the tibia and trends in the femur. Additionally, increased periosteal bone formation was observed in the femurs of SCI‐HU‐308 treated animals following the delayed treatment (P < 0.05) and absent in the SCI‐VEH treated animals. We also sectioned undecalcified bone and stained with Alizarin to demonstrate preservation and rebuilding of bone with HU‐308 in the acute and delayed treatment paradigms. Acutely, there appears to be preservation of the cortical bone and not the trabecular bone; the VEH‐treated mice showed loss of mineralization in both trabecular and cortical bone. Delayed treatment with HU‐308 shows bone formation with a higher degree of trabecular and cortical mineralization in comparison to VEH‐treated SCI mice. Taken together these data suggest that the cannabinoid system contributes to the pathophysiology of SCI‐induced osteoporosis and that CB2 agonism may be a viable therapeutic strategy to prevent or slow osteoporosis in SCI patients. Support or Funding Information This work is supported by Department of Defense Grant Award Number: W81XWH‐16‐1‐0349 to BEG.