[Show abstract][Hide abstract] ABSTRACT: To evaluate the effects of various 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on ectopic osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2) using different administration methods.
Disks containing 5 mug of rhBMP-2 and type I collagen were implanted into the calf muscles of 6-week-old male rats (n = 64). Either the lactone form of simvastatin (SV), open hydroxy-acid form of simvastatin (SVA), cerivastatin (CVA), or vehicle (control) was then administered per orally (PO group) or subcutaneously (SC group) for 20 days. The disks were removed on day 21 after implantation, and ectopic induced bone formation was evaluated by radiographic, histologic, and biochemical analysis.
Both the projected and radiopaque area on X-ray film, and the calcium content of the SV group in the SC group (SV-SC group) were significantly greater than those in the other SC and PO groups. Alkaline phosphatase activity and tartrate-resistant acid phosphatase activity in the SV-SC group were significantly lower than those in the other SC and PO groups. Histologic examination revealed an increase of ectopic induced bone volume in the SV-SC group.
Subcutaneous administration of SV stimulates ectopic osteoinduction by rhBMP-2 through reduction of bone turnover.
[Show abstract][Hide abstract] ABSTRACT: To investigate the characteristics of ectopic chondroid/bone matrix and chondrogenic/osteogenic cells induced by recombinant human bone morphogenetic protein-2 (rhBMP-2).
rhBMP-2 (5 microg) combined with atelocollagen was implanted into calf muscles of rats and removed on days 7, 10, 14, 21, or 28. Tissue sections were examined using: (i) hematoxylin/Alcian blue/Sirius red stain, (ii) enzyme histochemistry for alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase activity, (iii) immunohistochemistry for types I, II, and X collagen, and (iv) electron microscopy.
On day 7, numerous fibroblast-like cells with ALP activity were present on the pellet rim. On day 10, chondroid matrix (CM) had formed, contained both type I collagen and proteoglycans, and often continued into the BMP pellet. On day 14, bone-like matrix formed around hypertrophic chondrocytes simultaneously with endochondral ossification. Coexpression of types I and II collagen within chondrocytes and osteocytes was observed throughout the time course of the experiment.
These results suggest that fibroblast-like cells invading the pellet differentiate into chondrocytes and form CM under the scaffold of the carrier component. It appears that some chondrocytes change their phenotype to produce the bone-like matrix and remain within the endochondral bone. This process enables rapid osteogenesis to occur.