THYROID AND ARTICULAR CARTILAGE REPAIR IN DOG AND SHEEP BY OP-1 (1998)

Repair of articular cartilage remains an unsolved but formidable challenge. However, as joint defects are exposed to increased mechanical forces it is difficult to prevent full mechanical loading of surgically created defects in animals. Therefore, we first studied a possible role of OP-1 in regeneration of the thyroid cartilage which forms an essential part of the larynx. The thyroid cartilage is a permanent hyaline cartilage expossed to significantly less mechanical strain as compared to articular cartilage. Thyroid cartilage defects (1.5 cm2) created in dogs were treated with thyroid allografts covered with host perichondrium. Prior to implantation allografts were frozen, thawed and demineralized. The treatment groups were as follows: I/ Allograft control implant (n=3); II/ Implants coated with 500 mg OP-1 (n=4); III/ Implants coated with 100 mg OP-1 (n=3); and IV/ Implants extracted with 1M NaCl and guanidine hydrochloride, and coated with 500 mg OP-1 (n=3). Dogs were killed four months following surgery. Unlike control implants, OP-1 enriched thyroid allografts, dose dependently induced bone, cartilage and ligament-like structures suggesting that OP-1 served as a multiple tissue morphogen in this specific microenvironment. Boundary areas lacking bone inside cartilage layers healed by formation of cartilage, with excellent integration of new and old cartilage. The regenerated cartilage was well integrated with the pre-existing cartilage, suggesting that OP-1 can promote stable remodeling of cartilage matrix. Next, the efficacy of OP-1 in regeneration of articular cartilage was examined by treating knee chondral defects (10 mm) in sheep with OP-1. OP-1 was delivered via an extraarticularly positioned Alzet mini-osmotic pump. A total amount of 55 mg (low dose) or 165 mg (high dose) OP-1 in acetate buffer was slowly released from the pump over a period of two weeks following surgery. Six sheep were treated with the low OP-1 dose and six with the high OP-1 dose, and three of each were killed either at three or six months following surgery. The animals were observed every three weeks by artroscopy. At three months following surgery defects treated with both OP-1 doses were filled with tissue comprising of dense connecting tissue and cartilage. At six months following surgery both doses of OP-1 stimulated macroscopically almost complete regeneration in 9 out of 12 defects. The boundaries between new and old cartilage were fused and mechanically resisted animals' full activity. The regenerated cartilage was rich in proteoglycans and type II collagen as demonstrated by toluidine blue staining and immunohistochemistry. No signs of endochondral bone formation above well preserved bony tidemarks were observed unless cells from bone marrow occupied the defect site. We suggest that in the presence of full mechanical loading OP-1 stimulates ingrowth of synovial cells into the chondral defects which are capable to transform into a full thickness columnar, proteoglycan rich articular chondrocytes. In conclusion, OP-1 regenerated both thyroid and articular cartilage defects inducing multiple tissues in two different microenvironments.