Production of parathyroid hormone‐related peptide by synovial fibroblasts in human osteoarthritis

Abstract

Synovial fibroblasts from patients with osteoarthritis in culture produced parathyroid hormone-related peptide (PTHrP) on treatment with phorbol ester (TPA) in a doseand time-dependent manner. The levels of PTHrP immunoreactivity in the conditioned medium of synovial fibroblast cultures were measured using specific PTHrP antibody. The maximum production was obtained at a concentration of 10 -8 M and 24 h after TPA treatment. But sensitivity to TPA of synovial fibroblasts differed among four patients from slight to marked. PTHrP production was also induced with inflammatory cytokines, such as 1 nglml of IL-lcx, IL-113, IL-6 and TNF-~ and 10 -6 M prostaglandin E2, after 24 h treatment. The expression of PTHrP was confirmed by reverse-transeriptase polymerase chain reaction. Since the synovial fibroblasts isolated from osteoarthritic patients produce high levels of IL-6 and IL-8, typical cytokines produced in synovial fibroblasts, production of PTHrP may provide new insight into the pathophysiology of joint disorder.© 1998 Federation of European Biochemical Societies.Key words: Parathyroid hormone-related peptide; Osteoarthritis; Synovial fibroblast; Cytokine; Phorbol ester; Human endothelial cells in blood vessels, were demonstrated to express PTHrP by immunohistochemistry [9]. However, it has not yet been determined whether PTHrP is actually produced in synovial cells established from synovial membrane in culture. Synovial fibroblasts, abundant components of the synovial membrane, proliferate markedly in arthritis and cause hypertrophy. Then, synovial fibroblasts isolated from synovial membrane of osteoarthritis were established in culture, and examined for PTHrP production in the presence or absence of activating factors such as phorbol ester, inflammatory cytokines and prostaglandin E2 (PGE2). In this study we demonstrate that production of PTHrP was induced in synovial fibroblasts with not only phorbol ester TPA, but also inflammatory cytokines and PGE2. PTHrP influences the proliferation of lymphocytes [10], and the N-terminal peptide portion (1-34) acts as a stimulator of in vivo bone resorption when applied intermittently to neonatal mice [11]. Our findings suggested that PTHrP produced by synovial fibroblasts plays a novel role as a paracrine/autocrine factor in the pathophysiology of osteoarthritis. Materials and methods

Sequential changes of parathyroid hormone related protein (PTHrP) in articular cartilage during progression of inflammatory and degenerative arthritis

“…Immunoreactive PTHrP levels in synovial fluid are higher in patients with RA than in those with OA, suggesting that synovial PTHrP levels may reflect the disease activity, but its true effect on the diseased articular cartilage is unknown. [20][21][22] When immunohistochemical staining and in situ hybridisation were used, PTHrP was detected in diseased cartilage chondrocytes, both in RA and OA, suggesting that it has a role in these pathological conditions. 11 13 In our study, cartilage PTHrP was immunolocalised in two well established rabbit models of inflammatory and degenerative arthritis.…”

PTHrP overexpression partially inhibits a mechanical strain-induced arthritic phenotype in chondrocytes

“…Although PTHrP is known to stimulate NO release from endothelial cells for local regulation of vascular tone43, a possible mechanism for PTHrP-mediated NO release in chondrocytes has not been elucidated. Additionally, studies have found that PGE 2 increases PTHrP production in chondrocytes44, 45, but the reverse has not been reported. Increased production of pro-inflammatory intermediaries is expected to promote apoptosis through regulation of Bcl-2 and Bax gene expression in chondrocytes.…”

E1A oncogene expression inhibits PTHrP P3 promoter activity and sensitizes human prostate cancer cells to TNF-induced apoptosis

“…The main goal of this experiment was to test the ability of E1A to convert PC-3 prostate cancer cell line from the apoptosisresistant to the apoptosis-sensitive phenotype. PTHrP is expressed by many types of epithelial cells, and this expression can be induced by cytokines and growth factors [21][22][23][24][25][26]. In contrast, expression can become unregulated in certain neoplasms, including but not restricted to prostate cancer.…”