Prostaglandins in inflammatory bone pathology: mechanism and therapeutic benefit of etodolac.
To investigate the role of PGE2 in the development of bone and joint pathology in rat adjuvant arthritis, hindlimb paws were evaluated by calcified tissue histologic techniques focusing on histochemical visualization of cartilage and bone lesions. Case studies of hindlimbs from normal, adjuvant arthritic, and etodolac-treated arthritic rats demonstrated the association of disease severity with inflammation, chondromalacia, replacement of adipose bone marrow with a fibroid marrow, osteoclastic bone resorption, synovial cysts, and pannus formation within the joints. Extensive periosteal intramembranous bone formation was temporally associated with joint destruction and medullary tissue pathology. In vivo data were correlated with in vitro effects of inflammatory mediators (IL-1, PGE2) on bone resorption. Etodolac blocked bone explant PGE2 accumulation at concentrations of 10(-7) M and higher, and inhibited bone resorption at concentrations of 10(-5) M and higher. The data indicate that in vitro and in vivo models of bone metabolism are well correlated regarding prostaglandin synthesis; that the inflammatory mediator PGE2 is largely responsible for the involvement of skeletal tissue in the adjuvant arthritis model; and that the effects of etodolac are specifically mediated by its ability to inhibit PGE2 accumulation in vivo.
Hayward
M A
MA
Wyeth-Ayerst Research, CN 8000, Princeton, NJ 08543.
Howard
G A
GA
Neuman
R G
RG
Wood
D D
DD
Weichman
B M
BM
Van Sickle
D C
DC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001168:Arthritis / Q000473:pathology*; D001169:Arthritis, Experimental / Q000473:pathology* / Q000517:prevention & control; D001847:Bone Diseases / Q000473:pathology* / Q000517:prevention & control; D001862:Bone Resorption / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D017308:Etodolac; D007210:Indoleacetic Acids / Q000627:therapeutic use*; D007249:Inflammation; D008297:Male; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007210:Indoleacetic Acids; D011453:Prostaglandins; D017308:Etodolac