ABSTRACT
Unloading, neural lesions, and hormonal disorders after acute motor-complete spinal cord injury (SCI) cause one of the most severe forms of bone loss, a condition that has been refractory to available interventions tested to date. Thus, these features related to acute SCI provide a unique opportunity to study complex bone problems, potential efficacious interventions, and mechanisms of action that are associated with these dramatic pathological changes. This study was designed to explore the therapeutic potential of sclerostin antibody (Scl-Ab) in a rat model of bone loss after motor-complete SCI, and to investigate mechanisms underlying bone loss and Scl-Ab action. SCI rats were administered Scl-Ab (25 mg/kg/week) or vehicle beginning 7 days after injury then weekly for 7 weeks. SCI resulted in significant decreases in bone mineral density (-25%) and trabecular bone volume (-67%) at the distal femur; Scl-Ab completely prevented these deteriorations of bone in SCI rats, concurrent with markedly increased bone formation. Scanning electron microscopy revealed that SCI reduced numbers of osteocytes and dendrites concomitant with a morphology change from a spindle to round shape; Scl-Ab corrected these abnormalities in osteocytes. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increases in mRNA levels of LRP5, osteoprotegerin (OPG), and the OPG/RANKL ratio, and a decrease in DKK1 mRNA. Our findings provide the first evidence that robust bone loss after acute motor-complete SCI can be blocked by Scl-Ab, at least in part, through the preservation of osteocyte morphology and structure and related bone remodeling. Our findings support the inhibition of sclerostin as a promising approach to mitigate the striking bone loss that ensues after acute motor-complete SCI, and perhaps other conditions associated with disuse osteoporosis as a consequence of neurological disorders.
Subject(s)
Antibodies/pharmacology , Bone Morphogenetic Proteins/immunology , Femur/pathology , Genetic Markers/immunology , Osteocytes/pathology , Spinal Cord Injuries/pathology , Animals , Cell Count , Femur/drug effects , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Male , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Osteoblasts/drug effects , Osteoblasts/pathology , Osteoclasts/pathology , Osteocytes/drug effects , Osteocytes/metabolism , Osteogenesis/drug effects , Rats, Wistar , Spinal Cord Injuries/metabolismABSTRACT
OBJECTIVE: To study the different effects of crude Atractylodis Rhizoma and processed Atractylodis Rhizoma in healthy rats, in order to prove the traditional theory that the crude Atractylodis Rhizoma has dry effects and the dry effects can be weaken by processing. METHODS: Health rats had been orally administered with pure water, crude Atractylodis Rhizoma, processed Atractylodis Rhizoma and atropine. The concentration of AQP1 and AQP5 in submaxillary gland were measured by ELISA. Their index of submaxillary gland, hemorheology and moisture content of intestine were also measured. RESULTS: There were obvious differences of concentration of AQP1 and AQP5 in submaxillary gland, index of submaxillary gland, hemorheology and moisture content of intestine between the rats which had been orally administered crude Atractylodis Rhizoma and the rats administered processed Rhizoma Atractylodes. CONCLUSIONS: The dry effects of Atractylodis Rhizoma works on rats' moisture content of intestine, index of submaxillary gland and hemorheology. The dry effects can be weaken by processing.