Osteoclast-like Multinucleated Giant Cells Research Articles

Primary giant cell tumor of soft tissue.

Primary giant cell tumor of soft tissue, also known as soft tissue giant cell tumor of low malignant potential, is a rare soft tissue tumor located in both superficial and deep soft tissue. Histologically, these lesions bear a close resemblance to their bony counterparts, giant cell tumor of bone, with round to spindle-shaped cells intimately admixed with uniformly scattered osteoclast-like multinucleated giant cells. In 1989 in the dermatology literature, two malignant giant cell tumors of soft parts were described that filled the dermis and extended into the subcutaneous tissue. The authors report the rare occurrence of a giant cell tumor of soft tissue occurring primarily in the dermis that lacks overtly malignant features and clinically was thought to be an epidermal inclusion cyst. Light microscopy revealed a non-encapsulated cellular dermal tumor containing numerous osteoclast-like giant cells. Cytologic atypia was minimal and the mitotic count averaged 2-3/10 HPF. The histologic differential diagnosis is also discussed. Giant cell tumor of soft tissue is a rare neoplasm of the skin, however, recognition of this tumor is important due to its behavior as a low-grade malignancy.

The nature of giant cell tumor of bone.

Giant cell tumor of bone (GCT) is a locally osteolytic tumor with variable aggressiveness. In rare cases, pulmonary metastasis can be observed. The lesion most frequently occurs in the epiphysis of long tubular bones of the knee region, predominantly affecting young adults after closure of the growth plate. The characteristic histological appearance of GCT displays a high number of osteoclast-like multinucleated giant cells, which resulted in the classification "osteoclastoma" or "giant cell tumor". Apart from the multinucleated giant cells, there are two mononuclear cell types in GCT. The first one has a round morphology and resembles monocytes. The second cell type is the spindle-shaped, fibroblast-like stromal cell. Cell culture experiments with GCT cells revealed the stromal cell to be the proliferating component of the GCT. The other two cell types, the monocyte and the multinucleated giant cell, were lost after a few cell culture passages. Furthermore, latest results from GCT reveal that the stromal cells secrete a variety of cytokines and differentiation factors, including MCP1, ODF, and M-CSF. These molecules are monocyte chemoattractants and are essential for osteoclast differentiation, suggesting that the stromal cell stimulates blood monocyte immigration into tumor tissue and enhances their fusion into osteoclast-like, multinucleated giant cells. The multinucleated giant cell itself resembles a normal osteoclast that is able to resorb bone leading to extended osteolysis. This new model of GCT genesis supports the hypothesis that the stromal cell is the neoplastic component whilst the monocytes and the multinucleated giant cells are just reactive components of this tumor. Taking this into consideration, the nomenclature of the "giant cell tumor" needs to be reconsidered.

Breast carcinoma with osteoclast-like giant cells: morphological and ultrastructural studies of a case with review of the literature

Primary carcinoma with osteoclast-like giant cells is a very rare tumour of the female breast. The clinical course, histological, immunohistochemical and ultrastructural features of 61 cases of invasive duct carcinoma with osteoclast-like multinucleated giant cells (OMGCs) are reviewed and a new case is presented. The median patient age of all patients included in the review was 42 years, the tumour was located in the upper outer quadrant and the mammographic and gross findings were of a well-defined tumour of dark-brown colour, resembling a metastatic melanoma. Follow-up data in the literature have shown that 86% of patients with these tumours are still alive after 5 years.Histologically, these tumours are invasive ductal carcinomas with OMGCs next to the neoplastic glands and within their lumen. Signs of recent and past haemorrhage are ubiquitously present in the highly vascularized stroma. Immunohistochemical and ultrastructural studies have claimed a benign histiocytic nature of the OMGCs; they may represent a special type of polykaryon, distinct from both osteoclasts and inflammatory giant cells.

Chondroblastoma-like chondroma of soft tissue: an underrecognized variant and its differential diagnosis.

Soft-tissue chondromas are usually composed entirely of mature hyaline cartilage. Infrequently, however, they may exhibit morphologic features that result in diagnostic difficulty. The authors report a series of eight hypercellular soft-tissue chondromas composed of enlarged chondrocytes within a variable amount of chondroid matrix that often demonstrated delicate calcifications and contained numerous osteoclast-like multinucleated giant cells. This histologic appearance closely resembles that of chondroblastoma of bone. However, its extraosseous location, dense cellularity, and poorly formed cartilage can cause confusion with more aggressive chondroid neoplasms of soft tissue. The clinicopathologic features of these chondroblastoma-like chondromas are discussed, emphasizing the characteristics that facilitate their accurate identification.

The histogenesis of giant cell tumour of bone: a model of interaction between neoplastic cells and osteoclasts.

Giant cell tumour of bone (GCT) is a benign primary neoplasm of a bone characterised by distinctive clinical, radiological and pathological features. Females are slightly more often affected than males, and the majority of patients present between the ages of 20 and 50. GCT is locally aggressive and produces expansive and lytic lesions, most commonly in the epiphyses of long tubular bones. Histologically, it is composed of oval and spindle mononuclear cells, uniformly distributed amongst which are large multinucleated osteoclast-like giant cells. Although the term "Giant Cell Tumour" (and the erroneous historical term 'osteoclastoma') may imply that it is the multinucleated giant cells which are responsible for the proliferative capacity of the tumour, there is evidence that the stromal-like cells, the major component of the mononuclear cell population, represent the true neoplastic component of the neoplasm. The diagnosis and management of conventional GCT are often challenging and there is considerable current interest in its pathobiology. The precise histogenesis of GCT and the nature of its varying cellular constituents have remained a matter of some controversy. Factors influencing the clinical course and biological aggression of GCT are also unclear. In this selective review, the clinicopathological characteristics of GCT are summarised and current areas of interest in the study of the neoplasm are presented and discussed. Lastly, a hypothetical model of the mechanism of histogenesis and the biological behaviour of GCT is presented.

Angiotensin-converting enzyme, transforming growth factor beta(1), and interleukin 11 in the osteolytic lesions of Langerhans cell histiocytosis.

To assess the expression of potential osteoclastogenic and osteolytic factors in osteolytic lesions from patients with Langerhans cell histiocytosis. Paraffin-embedded biopsy sections from 5 such archival cases underwent immunohistochemical procedures with antibodies to detect the following antigens: CD(1a), S100 protein, interleukin 11, the latency-associated peptide of transforming growth factor beta(1), and angiotensin-converting enzyme. Commonalities noted include (1) the presence of multinucleated osteoclast-like giant cells, (2) the expression of interleukin 11 and latency-associated peptide antigens in lesional Langerhans cells, and (3) plasmalemmal immunoreactivity for angiotensin-converting enzyme antigen on non-Langerhans cell histiocytes and, on occasion, osteoclast-like giant cells and endothelial cells. These observations suggest a possible pathogenetic sequence for osteolysis in Langerhans cell histiocytosis that involves angiotensin II formation, leading to the activation of latent transforming growth factor beta(1) and, in turn, to the enhanced production of interleukin 11, resulting in both osteoclastogenesis and impaired remodeling of bone.

Ovarian serous adenocarcinoma with anaplastic areas containing osteoclast-like multinucleated giant cells

Ovarian tumors with osteoclast-like multinucleated giant cells are rarely encountered, and the existence of osteoclast-like giant cells in ovarian tumors may have no effect on the patients' prognosis. We report a patient with ovarian serous adenocarcinoma containing osteoclast-like multinucleated giant cells in the anaplastic areas of the tumor, who had a poor prognosis. A recurrent tumor showed the same anaplastic appearance as that of the primary tumor, with osteoclast-like giant cells. Forty-one percent of tumor cells were positive for MIB-1 (Ki-67) antigen, and many cells overexpressed p53 protein. However, the giant cells were negative for both antigens, which meant that they were non-cycling cells. The giant cells were also negative for epithelial and non-epithelial antigens. The multinucleated osteoclast-like giant cells, as well as mononucleated tumor cells around the giant cells, expressed p21 (WAF1/ClP1) protein. These findings suggest that the multinucleated osteoclast-like giant cells in this tumor originated from the p21-expressing mononuclear tumor cells. The coexistence of anaplastic foci with multinucleated giant cells in serous adenocarcinomas of the ovary may indicate a poor prognosis.

Gene expression of vascular endothelial growth factor in giant cell tumors of bone

The production of vascular endothelial growth factors (VEGF), a major cause of neoangiogenesis, is a prerequisite for tumor growth and invasion. VEGF have also been shown to be important for the formation of osteoclasts. Because giant cell tumors of bone (GCT) are frequently hypervascular and have the ability to recruit macrophages and multinucleated osteoclast-like giant cells, we evaluated the levels of VEGF gene transcript in several of these tumors using Northern blot analyses, semiquantitative reverse transcription polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry. Our results showed that three major isoforms of VEGF (121, 165, and 189) were expressed in all cases of GCT investigated, with isoform 121 transcripts the most abundant. By both FISH and immunohistochemistry, we have shown that VEGF was present in spindle-shaped stromal-like tumor cells, round macrophage-like cells, and osteoclast-like multinucleate giant cells. Moreover, we have shown that the levels of VEGF gene expression but not microvessel density correlated with Enneking's clinical stage of GCT. There were higher levels of VEGF gene expression in stage III GCT than in stage I/II GCT (P [lt ] .0357). In conclusion, our results indicate that overexpression of VEGF may be associated with the advanced stage of the neoplasm. HUM PATHOL 31:804-812.

Giant cell tumors of soft tissue: a clinicopathologic study of 18 benign and malignant tumors.

Primary giant cell tumors (GCTs) of soft tissue resembling osseous GCTs are uncommon but distinct entities. Malignant GCTs of soft tissue have been designated giant cell malignant fibrous histiocytomas; however, there is scant data regarding benign GCTs of soft tissue. Eleven benign and seven malignant GCTs of soft tissue were identified from the authors' consultation files and the surgical pathology files of the Vancouver General Hospital and Massachusetts General Hospital. The tumors occurred in adults (eight men, 10 women; age range, 25-89 years; mean age, 54 years) in the extremities (n = 14) and in the trunk, abdomen, and pelvis (n = 4). In each patient the skeleton was normal and there was no history of prior osseous GCT. Tumors ranged in size from 0.8 to 9.0 cm. Eleven occurred in the superficial soft tissue and seven occurred in deep soft tissue. Grossly they were circumscribed and frequently hemorrhagic. Cystic change was present in seven tumors. Nine tumors were partially surrounded by a shell of reactive bone. In all tumors, multinucleated osteoclast-like giant cells were distributed uniformly and evenly among mononuclear cells. The histologically benign GCTs of soft tissue were identical to typical osseous GCTs. The mononuclear cells in these tumors lacked nuclear atypia or pleomorphism, and the mitotic rate within this population was low (mean, three mitoses per 10 high-power fields [HPF]). In the malignant GCTs of soft tissue, the mononuclear cells exhibited anisocytosis, nuclear atypia, pleomorphism, and readily detectable mitoses including atypical forms (mean, 25 mitoses per 10 HPF). None of the benign or malignant tumors exhibited neoplastic bone production. The benign and malignant GCTs of soft tissue demonstrated a similar immunohistochemical staining profile to GCT of bone ( 12 tumors examined), exhibiting strong positive staining for CD68 within multinucleated osteoclastlike cells, and focal staining of mononuclear cells for CD68, Ham 56, and smooth muscle actin. All tumors were treated by surgical resection. Follow-up information is available for 15 patients (range, 0-108 months). No benign tumor has recurred or metastasized. Of the four patients with malignant tumors for whom follow-up information is available, one died of metastatic disease at 13 months and one developed a local recurrence at 84 months but is alive, apparently free of disease after additional excisional surgery. Primary GCTs of soft tissue are distinctive neoplasms that, like osseous GCTs, exhibit a wide clinicopathologic spectrum. These neoplasms should be distinguished from other giant cell-rich soft-tissue tumors with which they may be confused.

Breast Carcinoma with Osteoclast-like Giant Cells: A Case Report and Review of the Japanese Literature.

A 41-year-old premenopausal woman with a 3.5 cm freely mobile mass in the upper outer quadrant of the right breast was admitted to our hospital. Fine needle aspiration showed malignant epithelial cells and many multinucleated osteoclast-like giant cells (OGCs). Excisional biopsy revealed an invasive ductal carcinoma. A right modified radical mastectomy was subsequently performed. Macroscopically the tumor was well circumscribed with a dark brown cut surface. Microscopically, the tumor was a grade 2 invasive ductal carcinoma with many multinucleated OGCs adjacent the tumor cells and hemorrhage and infiltration of inflammatory cells in the stroma. The intra-mammary metastasis also contained OGCs and stromal reactions. By enzyme immunoassay, the tumor cells were negative for estrogen receptor but positive for progesterone receptor. The tumor cells were negative for both c-erbB-2 and p53. The OGCs showed positive immunostaining with the monoclonalantibody CD68, demonstrating a histiocytic origin. Lymph nodes were free of metastasis. We also review the Japanese literature concerning breast carcinoma withOGCs.

Telomeric fusion is a major cytogenetic aberration of giant cell tumors of bone

Giant cell tumor of bone (GCT) is regarded as a rare primary bone neoplasm derived from stromal cells, which have the ability to recruit and harbor macrophage and multinucleated osteoclast-like giant cells. Despite being often considered benign, GCT is a problematic neoplasm in that it is aggressive, unpredictable and difficult to treat effectively. Cytogenetically GCT is characterised by a high frequency of telomeric fusion, a process which has been implicated in the production of chromosome instability and tumorigenesis. To extend our knowledge of the significance of telomere association in GCT, the cytogenetics of cell lines derived from spindle-shaped stromal-like mononuclear cells (the tumor cells) of GCT was investigated. Cell lines from three different patients showed telomeric association in all passages. The rate of telomeric association varied from line to line and from passage to passage, but there was no particular pattern to the variations. Many other cytogenetic abnormalities were seen as well as telomeric association, but these were rarely clonal. The nature of most of the other abnormalities seen, such as deleted chromosomes and chromosomes with additional unidentifiable material, was consistent with their being formed as a result of breakage of the dicentric fused chromosomes at a telophase. Chromosomes 13, 14 and 21 were most commonly involved in telomeric fusion. It appears that telomeric association persists in long-term cultures of GCT and is responsible for the accumulation of other associated cytogenetic aberrations. Telomeric reduction and telomerase activity may act as oncogenic events, promoting and sustaining the transformed GCT phenotype.

Aggregation of mononucleated precursors triggers cell surface expression of alphavbeta3 integrin, essential to formation of osteoclast-like multinucleated cells.

Alphavbeta3 is a key integrin mediating adhesion of multinucleated osteoclasts during bone resorption. 1, 25-dihydroxyvitamin D3 upregulates alphavbeta3 integrin expression in mononucleated osteoclast precursors and concomitantly stimulates their differentiation into osteoclasts. This suggests that this integrin could play a major role during osteoclast differentiation. We have developed an in vitro model, in which 1, 25-dihydroxyvitamin D3 sequentially modifies the behavior of macrophages: It first induces rounding up of these cells, then their subsequent aggregation and spreading, which finally leads to cell fusion and the formation of osteoclast-like multinucleated giant cells. We show that, while 1,25-dihydroxyvitamin D3 stimulates the de novo synthesis of alphavbeta3 in macrophages early in this process, its accumulation on the surface is triggered by cell aggregation. A high level of integrin alphavbeta3 cell surface expression correlates with macrophage spreading preceding fusion. This was confirmed by means of novel cell permeable peptides containing the C-terminal sequence of the integrin beta3 tail to specifically block (alphavbeta3 function. Although this peptide has no effect on the aggregation step, it disrupts the spreading of osteoclast precursors and consequently inhibits their fusion. These findings suggest a novel role of the integrin alphavbeta3 in a discrete step of osteoclast differentiation.

Primary lung tumors infiltrated by osteoclast-like giant cells.

Six primary lung tumors with numerous multinucleated osteoclast-like giant cells (OLGCs) and no osteogenic component were evaluated histologically and immunohistochemically to examine pulmonary lesions inciting an OLGC response. The patients comprised four women and two men ranging in age from 61 to 80 years (average age, 69 years). The tumors consisted of one adenocarcinoma, two sarcomatoid carcinomas, and three giant cell variants of malignant fibrous histiocytoma. One tumor was endobronchial in location, while five were situated peripherally. Tumor diameter spanned from 1 to 6.5 cm (average, 2.7 cm). In addition to the giant cells, common characteristics included the malignant nature of the neoplasms and, in five of six cases, histologically malignant mesenchyme. This array of cases exemplifies the variability of lung lesions which may elicit an OLGC inflammatory response resulting in areas resembling the giant cell variant of malignant fibrous histiocytoma. The results of this study suggest that OLGCs occur preferentially in malignant rather than benign nonosteogenic lung tumors and that sarcomatoid regions of malignant tumors are more likely to be infiltrated by OLGCs than epithelial regions.

Induction of abundant osteoclast-like multinucleated giant cells in adjuvant arthritic rats with accompanying disordered high bone turnover.

The development of an in vivo system for investigating osteoclast differentiation is important because molecular events occurring in vivo can be observed during the differentiation of the authentic osteoclasts. In adjuvant arthritic rats, an experimental model of human rheumatoid arthritis, extensive bone resorption is observed in the distal diaphysis of the tibia. In the area of extensive bone resorption, it is always accompanied with clusters of numerous multinucleated giant cells (MGCs) as well as bone-resorbing osteoclasts. Here we characterized the morphological properties of these MGCs with the use of enzymehistochemical and immunohistochemical techniques. Extensive destruction but also a marked formation of the inner and outer bone surfaces were the predominant features in the tibiae of such arthritic rats 4 weeks after the adjuvant injection. Numerous MGCs were frequently clustered in the bone marrow spaces located apart from the bone matrices. Although the MGCs lacked ruffled borders, these cells were rich in mitochondria and vacuoles. These multinucleated cells revealed a positive reaction for tartrate-resistant acid phosphatase but a negative reaction for non-specific esterase staining. Most of these MGCs expressed the Kat 1-antigen, an immunological marker specifically expressed on the cell surface of rat osteoclasts. In a dentin resorption experiment using a cluster of MGCs excised from the bone marrow tissues of the tibial distal diaphyses of rats with adjuvant arthritis, many resorption lacunae were formed on dentin slices after a 3-day culture. These results suggest that the majority of the MGCs are osteoclasts but not macrophage polykaryons.

Giant-Cell Osteosarcoma in a Female Ranch Mink (Mustela Vision)

Osteosarcomas, malignant primary tumors of bone in which the major cell type is osteoblastic, form osteoid and often some cartilage.3,9 Various histological patterns are described. Osteosarcomas may resemble giant-cell tumor of bone, osteoblastoma, malignant fibrous histiocytoma of bone,8,10 ossifying fibroma, or fibrous dysplasia.6 Osteosarcomas are common in dogs and are occasionally found in other animal species.6,8,10 Only 2 osteosarcomas have been previously reported in mink, but no descriptive details were given.6 This report describes a giant-cell osteosarcoma of the lumbosacral vertebrae in a 2-year-old female pastel mink. The mink had shown progressive emaciation, dehydration, and urinary incontinence and was found dead. At necropsy, body condition was poor. The anogenital region was stained by urine and feces. Subcutaneous fat was absent, and there was marked generalized atrophy of skeletal muscles and serous atrophy of pericardial fat. A hard 4 3 3 3 1.5-cm white mass extended ventrally from the last lumbar to the sacral vertebrae. The ill-defined mass protruded into the pelvic cavity, compressing the rectum and the urethra. The cross section of the mass had a white, multilobulated pattern, containing areas of hemorrhage and necrosis. There was no macroscopic evidence of metastasis. Specimens of the tumor and of all major organs were fixed in 10% neutral buffered formalin. Paraffin-embedded sections 5 mm thick were stained with hematoxylin–phloxine– saffron. The neoplastic mass was covered ventrally by a thin fibrous capsule and sparse remnants of normal bone. Demarcation between normal bone and neoplastic tissue was indistinct. The tumor was composed of 2 cell populations. One population consisted of osteoblast-like cells. These were polygonal to spindle-shaped cells, generally arranged in disorganized bundles (Fig. 1). The cytoplasm was lightly basophilic, and nuclei were hypochromatic, ovoid to irregular, and elongated. Pleomorphism was marked, anisokaryosis was moderate, and mitoses were rare. The other population consisted of prominent osteoclastlike multinucleated giant cells that made up 10–20% of the tumor cells (Fig. 1). These giant cells were more numerous around spicules of bone. These cells had 5–35 uniformly sized, generally ovoid nuclei. The cytoplasm was lightly acidophilic with an occasionally irregular outline. Some randomly distributed giant cells were necrotic. The stroma of the mass contained a few irregular spicules of focally mineralized osteoid. Well-defined, partly miner-

A New Cytokine-Dependent Monoblastic Cell Line With t(9;11)(p22;q23) Differentiates to Macrophages With Macrophage Colony-Stimulating Factor (M-CSF) and to Osteoclast-Like Cells With M-CSF and Interleukin-4

Monocytes/macrophages exert a series of important functions in vivo. To facilitate detailed investigation of their functional capacity and the mechanism leading to their differentiation, several cell lines have been established from primary material. We present here a new human monoblastic cell line, designated UG3. UG3 cells are characterized by the following features. (1) UG3 cells harbor the t(9;11)(p22;q23) translocation that results in fusion of the MLL and the AF9 genes and produce the corresponding AF9-MLL and MLL-AF9 fusion transcripts. (2) UG3 cells rely on the presence of exogenous growth factors for viability and proliferation, such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), or macrophage colony-stimulating factor (M-CSF). (3) When cultured in the presence of G-CSF, UG3 cells differentiate along the granulocytic lineage, as evidenced by segmentation of nuclei and positive staining for neutrophilic alkaline phosphatase and peroxidase. (4) When cultured in the presence of GM-CSF or M-CSF, UG3 cells differentiate into mature macrophages while preserving surface expression of CD14 and CD68 and also start to release cytokines into cell-culture supernatants. Under these culture conditions, UG3 cells also take up acetylated LDL. (5) When cultured in the presence of M-CSF and IL-4, UG3 cells differentiate into osteoclast-like multinucleated giant cells capable of bone resorption and display tartrate-resistant acid phosphatase (TRAP) activity. UG3 cells thus provide features to qualify them as a useful model to further investigate the mechanism underlying these processes and also to further elucidate the functional role of mature monocytes/macrophages or osteoclasts.

A New Cytokine-Dependent Monoblastic Cell Line With t(9;11)(p22;q23) Differentiates to Macrophages With Macrophage Colony-Stimulating Factor (M-CSF) and to Osteoclast-Like Cells With M-CSF and Interleukin-4

AbstractMonocytes/macrophages exert a series of important functions in vivo. To facilitate detailed investigation of their functional capacity and the mechanism leading to their differentiation, several cell lines have been established from primary material. We present here a new human monoblastic cell line, designated UG3. UG3 cells are characterized by the following features. (1) UG3 cells harbor the t(9;11)(p22;q23) translocation that results in fusion of the MLL and the AF9 genes and produce the corresponding AF9-MLL and MLL-AF9 fusion transcripts. (2) UG3 cells rely on the presence of exogenous growth factors for viability and proliferation, such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), or macrophage colony-stimulating factor (M-CSF). (3) When cultured in the presence of G-CSF, UG3 cells differentiate along the granulocytic lineage, as evidenced by segmentation of nuclei and positive staining for neutrophilic alkaline phosphatase and peroxidase. (4) When cultured in the presence of GM-CSF or M-CSF, UG3 cells differentiate into mature macrophages while preserving surface expression of CD14 and CD68 and also start to release cytokines into cell-culture supernatants. Under these culture conditions, UG3 cells also take up acetylated LDL. (5) When cultured in the presence of M-CSF and IL-4, UG3 cells differentiate into osteoclast-like multinucleated giant cells capable of bone resorption and display tartrate-resistant acid phosphatase (TRAP) activity. UG3 cells thus provide features to qualify them as a useful model to further investigate the mechanism underlying these processes and also to further elucidate the functional role of mature monocytes/macrophages or osteoclasts.

Generation of CD1+RelB+ Dendritic Cells and Tartrate-Resistant Acid Phosphatase-Positive Osteoclast-Like Multinucleated Giant Cells From Human Monocytes

We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) stimulate the differentiation of human monocytes into two phenotypically distinct types of macrophages. However, in vivo, not only CSF but also many other cytokines are produced under various conditions. Those cytokines may modulate the differentiation of monocytes by CSFs. In the present study, we showed that CD14+ adherent human monocytes can differentiate into CD1+relB+ dendritic cells (DC) by the combination of GM-CSF plus interleukin-4 (IL-4) and that they differentiate into tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like multinucleated giant cells (MGC) by the combination of M-CSF plus IL-4. However, the monocyte-derived DC were not terminally differentiated cells; they could still convert to macrophages in response to M-CSF. Tumor necrosis factor-alpha (TNF-alpha) stimulated the terminal differentiation of the DC by downregulating the expression of the M-CSF receptor, cfms mRNA, and aborting the potential to convert to macrophages. In contrast to IL-4, interferon-gamma (IFN-gamma) had no demonstrable effect on the differentiation of monocytes. Rather, IFN-gamma antagonized the effect of IL-4 and suppressed the DC and MGC formation induced by GM-CSF + IL-4 and M-CSF + IL-4, respectively. Taken together, these results provide a new aspect to our knowledge of monocyte differentiation and provide evidence that human monocytes are flexible in their differentiation potential and are precursors not only of macrophages but also of CD1+relB+DC and TRAP-positive MGC. Such a diverse pathway of monocyte differentiation may constitute one of the basic mechanisms of immune regulation.

Osteoclastoma-like Giant Cell Tumor of the Lung.

The main components of an unusual form of lung tumor were osteoclast-like multinucleated giant cells and mononuclear stromal cells. Besides, scattered islands of moderately differentiated squamous cells also appeared. Both the mononuclear and the osteoclast-like giant cells reacted with antibodies against CD68 and vimentin, but did not react with antibodies against cytokeratin, EMA and CEA, or lysozyme and a-1-antitrypsin. The p53 and PCNA antigens were positive only in mononuclear cells and not the osteoclast-like giant cells, suggesting that mononuclear cells represent proliferating elements with histiocytic differentiation while osteoclast-like giant cells are stromal, presumably reactive components of the tumor.

Production of interleukin-6 by human osteoclast-like cells from giant cell tumor of bone

Giant cell tumor (GCT) is a bone neoplasm which is characterized by the presence of large numbers of multinucleated osteoclast-like giant cells. Although GCT can be considered a benign lesion, it exhibits high local aggressiveness often associated with osteolytic properties. In this study, we used five different GCT primary cell cultures to evaluate whether osteoclast-like cells from GCT are able to produce interleukin-6 (IL-6), a cytokine strictly involved in the induction of osteoclast-mediated bone resorption. IL-6 assessment with ELISA revealed that osteoclast-like GCT cells produce low levels of this cytokine, which can be greatly increased after treatment with both lipopolysaccharide (LPS) or interleukin-1 beta (IL-1 beta). These data were confirmed by molecular analysis which revealed that GCT cells synthesize IL-6 mRNA and that the levels of IL-6 transcripts are greatly increased after treatment with both LPS and IL-1 beta. Moreover, by using a biologic assay with the 7TD1, a IL-6 dependent cell Line, we also determined that IL-6 synthesized by GCT cells is biologically active. This study supports the hypothesis that IL-6 locally released by GCT osteoclast-like cells may be involved in the induction of the osteolysis which is strictly associated with the biologic aggressiveness of GCT cells.