Association between sclerostin and bone density in chronic spinal cord injury.
ABSTRACT Spinal cord injury (SCI) results in profound bone loss due to muscle paralysis and the inability to ambulate. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short-term studies in rodent models have shown increased sclerostin in response to mechanical unloading that is reversed with reloading. These studies suggest that complete spinal cord injury, a condition resulting in mechanical unloading of the paralyzed lower extremities, will be associated with high sclerostin levels. We assessed the relationship between circulating sclerostin and bone density in 39 subjects with chronic SCI and 10 without SCI. We found that greater total limb bone mineral content was significantly associated with greater circulating levels of sclerostin. Sclerostin levels were reduced, not elevated, in subjects with SCI who use a wheelchair compared with those with SCI who walk regularly. Similarly, sclerostin levels were lower in subjects with SCI who use a wheelchair compared with persons without SCI who walk regularly. These findings suggest that circulating sclerostin is a biomarker of osteoporosis severity, not a mediator of ongoing bone loss, in long-term, chronic paraplegia. This is in contrast to the acute sclerostin-mediated bone loss shown in animal models of mechanical unloading in which high sclerostin levels suppress bone formation. Because these data indicate important differences in the relationship between mechanical unloading, sclerostin, and bone in chronic SCI compared with short-term rodent models, it is likely that sclerostin is not a good therapeutic target to treat chronic SCI-induced osteoporosis.
Article: Spinal cord injury causes rapid osteoclastic resorption and growth plate abnormalities in growing rats (SCI-induced bone loss in growing rats).[show abstract] [hide abstract]
ABSTRACT: Spinal cord injury causes severe bone loss. We report osteoclast resorption with severe trabecular and cortical bone loss, decreased bone mineral apposition, and growth plate abnormalities in a rodent model of contusion spinal cord injury. These findings will help elucidate the mechanisms of osteoporosis following neurological trauma. Limited understanding of the mechanism(s) that underlie spinal cord injury (SCI)-induced bone loss has led to few treatment options. As SCI-induced osteoporosis carries significant morbidity and can worsen already profound disability, there is an urgency to advance knowledge regarding this pathophysiology. A clinically relevant contusion model of experimental spinal cord injury was used to generate severe lower thoracic SCI by weight-drop (10 g x 50 mm) in adolescent male Sprague-Dawley rats. Body weight and gender-matched naïve (no surgery) rats served as controls. Bone microarchitecture was determined by micro-computed tomographic imaging. Mature osteoclasts were identified by TRAP staining and bone apposition rate was determined by dynamic histomorphometry. At 10 days post-injury we detected a marked 48% decrease in trabecular bone and a 35% decrease in cortical bone at the distal femoral metaphysis by micro-CT. A 330% increase in the number of mature osteoclasts was detected at the growth plate in the injured animals that corresponded with cellular disorganization at the chondro-osseous junction. Appositional growth studies demonstrated decreased new bone formation with a mineralization defect indicative of osteoblast dysfunction. Contusion SCI results in a rapid bone loss that is the result of increased bone resorption and decreased bone formation.Osteoporosis International 06/2008; 19(5):645-52. · 4.58 Impact Factor