Prostaglandins in inflammatory bone pathology: Mechanism and therapeutic benefit of etodolac

Abstract

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.

A comparison of clodronate and indomethacin in the treatment of adjuvant arthritis

“…Histopathological findings of the nondecalcified tarsus with ankle, intertarsal and tarsometatarsal joints showed that 56% of arthritic rats developed severe and 44% moderate arthritis on day 28 after immunization. All animals had synovitis and inflammatory articular lesions in the joint regions and excessive bone resorption and proliferative new bone formation, as has also been described by others [1,2,[19][20][21][22][23].…”

“…The sections (5 m thick) were stained using the Masson-Goldner trichrome method and the von Kossa method with hematoxylin/McNeal's tetrachrome counterstain [18]. Based upon histological studies in adjuvant arthritis [2,[19][20][21][22], a modified scoring system of hindpaws with a scale from 1 to 75 was used. This system allows differentiation of the severity of the changes, and is described in detail in our previous study [9].…”

Inhibitory effects of JTE-522, a novel prostaglandin H synthase-2 inhibitor, on adjuvant-induced arthritis and bone changes in rats

“…Development of secondary swelling coincides with prostaglandin E 2 (PGE 2 ) production associated with the upregulation of PGHS-2 mRNA and protein in arthritic paw, but with little upregulation of PGHS-1 [15]. Furthermore, large amounts of PGE 2 are released from PGHS-2 expressing synovial tissue [15][16][17] and PGE 2 is responsible for the increase in bone resorption in the chronic stage of adjuvant-induced arthritis rats [18]. It has been also reported that PGE 2 itself induces PGHS-2 mRNA expression and PGE 2 production in cultured bone [19], and IL-1b stimulates osteoclast-like cell formation from bone marrow cells via PGE 2 production by a PGHS-2-dependent mechanism [20].…”