Differential expression of transforming growth factor‐α and macrophage colony‐stimulating factor/colony‐stimulating factor‐1R (c‐fms) by multinucleated giant cells involved in pathological bone resorption at the site of orthopaedic implants

Abstract

The immunologic response to prosthetic biomaterial particles is characterized by macrophage-rich inflammatory infiltrate, formation of multinucleated giant cells, and aseptic loosening at the site of arthroplasty. We investigated the in vivo expression and tissue distribution of transforming growth factor alpha, macrophage colony-stimulating factor, and the receptor for colony-stimulating factor-1 at the site of bone erosion in patients with clinically failed orthopaedic implants (n = 30). The expression was further compared with that detected in the inflamed synovial membranes from patients with rheumatoid arthritis or osteoarthritis (n = 15) and one patient with osteoclastoma (giant cell tumour of bone). Immunostaining of the tissue demonstrated positivity for transforming growth factor alpha within the inflammatory macrophage and multinucleated giant cell infiltrate in the diseased synovial membrane and the bone-implant interface. A comparative analysis between the synovium and retrieval interface membranes (pseudosynovium) revealed a high level of expression of transforming growth factor alpha, with intense membrane staining on multinucleated giant cells in all failed arthroplasties with pseudosynovium. In addition, the frequency, antigenic phenotype, and pattern of transforming growth factor alpha expression on multinucleated giant cells in the interface were markedly similar to those observed for multinucleated giant cells in osteoclastoma. Multinucleated giant cells within the interface lacked the expression of macrophage colony-stimulating factor and colony-stimulating factor-1 receptor, whereas those at the bone surfaces exhibited strong immunoreactivity. The predominant expression of transforming growth factor alpha by multinucleated giant cells in the bone-implant interface and its similarity to osteoclastoma highlight the importance of assessing transforming growth factor alpha as a possible contributor to the development of bone-resorbing giant cells at the site of failed orthopaedic implants.

Prevention of Wear Particle-Induced Osteolysis by a Novel V-ATPase Inhibitor Saliphenylhalamide through Inhibition of Osteoclast Bone Resorption

“…The underlying mechanisms of particle-induced osteolysis are complex, involving numerous cytokines, chemokines, growth factors, and cell types. Wear particles stimulate macrophages, fibroblasts, foreign body giant cells, and T lymphocytes to release vast arrays of proinflammatory cytokines and chemokines including tumour necrosis factor-a (TNFα), interleukins-1, 6, 11 and 17 (IL-1, -6, -11, -17), prostaglandin E 2 (PGE 2 ) and macrophage-colony stimulating factor (M-CSF) all of which induce receptor activator of nuclear factor-κ B ligand (RANKL) expression by osteoblasts, marrow stromal cells and activated T-cells [4], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Increased RANKL levels at the implant site exacerbates the differentiation and activation of the already abundant pool of monocyte/macrophage precursors surrounding the prosthetic implant into mature osteoclasts thus shifting the local homeostasis to activated bone destruction [17], [18], [19], [20], [21].…”

The inflammatory potential of biphasic calcium phosphate granules in osteoblast/macrophage co-culture

“…It is also a contributory factor in the phenomenon of aseptic loosening in orthopaedic prosthesis. Advances in our understanding of this response, largely derived from various retrieval studies [1][2][3] has lead to investigations at a cellular level, leading to the conclusion that macrophages can be significant in determining the duration and intensity of the inflammatory response [4][5][6][7] and therefore as a driving mechanism behind the failure of a primary joint replacement caused by aseptic loosening. Due to this, several studies have investigated macrophage behaviour in response to exposure to various substrates and associated wear particles, both in vitro and in vivo, quantitatively and qualitatively [6][7][8][9][10][11][12][13][14][15][16][17].…”

Inhibition of colony-stimulating-factor-1 signalingin vivowith the orally bioavailable cFMS kinase inhibitor GW2580

“…CSF-1 promotes osteoclast development and bone degradation in vitro (11,12) and, thus, could contribute to the excessive osteoclast activity in osteoporosis and at sites of orthopedic implant failure (13,14). CSF-1 is elevated in the synovial fluid of rheumatoid arthritis patients (15), and synovial fibroblasts from rheumatoid arthritis patients produce high levels of CSF-1 (16), suggesting a role for CSF-1 in joint degradation.…”