ERK signaling regulates macrophage colony-stimulating factor expression induced by titanium particles in MC3T3.E1 murine calvarial preosteoblastic cells.

Periprosthetic osteolysis poses a significant clinical problem for patients who have undergone total joint arthroplastic surgeries. It has been widely recognized that there is a strong correlation between wear particles from orthopedic implants and osteolysis. However, the molecular mechanism underlying osteolysis still remains unclear. Although wear particles interact with a mixed cellular environment, namely macrophages and immune cells, osteoblasts compose the majority of the cell population surrounding orthopedic implants. Osteoblasts are also one of the major sources of receptor activator of nuclear factor-kappa beta (NF-kappaB) ligand (RANKL), a factor necessary for osteoclastogenesis. However, macrophage colony-stimulating factor (M-CSF), another cytokine responsible for preosteoclast proliferation, must also be present with RANKL for osteoclastogenesis to occur. The purpose of our study is to determine the signal transduction pathway by which titanium (Ti) particles, a metallic component of many orthopedic implants, induce M-CSF expression in MC3T3.E1 murine calvarial preosteoblastic cells. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme- linked immunosorbent assay (ELISA), our study demonstrated that submicron-sized Ti particles induce M-CSF expression via the extracellular signal-regulated kinase (ERK) pathway in a dose-dependent manner. Moreover, inhibition studies showed that a specific ERK inhibitor, PD98059, significantly downregulated M-CSF production. Our results support the hypothesis that submicron-sized Ti particles can induce M-CSF expression in osteoblasts and thus may have a significant role in contributing to the onset of periprosthetic osteolysis.

Orthopedic implant particle-induced tumor necrosis factor-alpha production in macrophage-monocyte lineage cells is mediated by nuclear factor of activated T cells.

Wear particles produced from artificial joint prostheses are known to cause macrophage-monocyte lineage cells to produce proosteoclastogenic cytokines, including tumor necrosis factor (TNF)-alpha. The specific molecular mechanism, however, is not yet known. Bioinformatic analysis showed that the promoter region of TNF-alpha has several consensus sequences for NFAT binding. Consequently, we examined the role of nuclear factor of activated T cells (NFAT) in TNF-alpha production. Our investigation has shown that treatment with titanium nanoparticles increased TNF-alpha gene expression along with TNF-alpha protein secretion in murine macrophage-like RAW264.7 and primary monocyte-macrophage cells. Titanium particle-induced TNF-alpha induction was inhibited by VIVIT, a peptide inhibitor that targets the calcineurin/NFAT axis, which suggests that NFAT mediates metallic particle-induced TNF-alpha expression in monocyte-macrophage lineage cells.

Nuclear factor of activated T cell mediates proinflammatory gene expression in response to mechanotransduction.

Bone adapts to its environment. Osteoblasts and osteocytes are subject to mechanical load in vivo. It has been shown that osteoblasts alter cytokine expression in response to mechanical loading. However, signal transduction pathways that mediate bone cell response to mechanical stimuli have not been elucidated. In this study, we report an increase in proinflammatory gene expression in response to fluid shear stress (FSS) in human mesenchymal stem cells (hMSCs) and mouse preosteoblasts. Fluid shear stress (FSS)-induced effect was blocked by the inhibition of the calcineurin-NFATc1 axis, thus implicating a role for nuclear factor of activated T cells (NFAT) signaling in mechanotransduction.

Extranodal Rosai-Dorfman disease of bone, subcutaneous tissue and paranasal sinus mucosa with a review of its pathogenesis.

We report an unusual case of extranodal Rosai-Dorfman disease presenting in a 36-year-old man with lesions of bone, subcutaneous tissue of the arm and maxillary sinus mucosa unassociated with lymphadenopathy or systemic symptoms. These lesions appeared metachronously within a 6-month period. The diagnostic light microscopic and immunohistochemical findings and pathogenesis of this interesting disease are discussed.

Synovial chondromatosis of the foot.

Synovial chondromatosis rarely occurs in the foot. Five patients with synovial chondromatosis in the foot were treated with excision. There were four men and one woman with a mean age of 37 years (range, 19-58 years). Mineral densities adjacent to the joint were seen on radiographs of all patients. Synovial chondromatosis occurred in the calcaneocuboid, tibiotalar, naviculocuneiform, and metatarsophalangeal joints. A painful mass was the common initial presentation in all patients. The patients were followed up for an average of 5 years (range, 3-16 years) after arthrotomy and excision. All patients were relieved of symptoms and retained normal function. There was no clinical or radiographic evidence of recurrence.