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The existence of a conjugate point on the volume-preserving diffeomorphism group of a compact Riemannian manifold Mis related to the Lagrangian stability of a solution of the incompressible Euler equation on M. The Misiołek curvature is a reasonable criterion for the existence of a conjugate point on the volume-preserving diffeomorphism group corresponding to a stationary solution of the incompressible Euler equation. In this article, we introduce a class of stationary solutions on an arbitrary Riemannian manifold whose behavior is nice with respect to the Misiołek curvature and give a positivity result of the Misiołek curvature for solutions belonging to this class. Moreover, we also show the existence of a conjugate point in the three-dimensional ellipsoid case as its corollary.

Recently, the US FDA approved sipuleucel-T, which is composed of autologous DCs stimulated with a recombinant fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF), as the first immunotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, sipuleucel-T demonstrated only modest efficacy in mCPRC patients. Researchers are now investigating the potential of p53 protein as a tumor-associated antigen (TAA) loaded in DC-based cancer vaccine. Approximately half of all tumors overexpress p53, and up to 20% of prostate cancer cells overexpresses p53. In this study, we evaluated the feasibility of combining p53-DC vaccine and rAd-p53 gene therapy, using the p53-overexpressing and non-expressing prostate cancer cells in vitro. We successfully generated the p53-DC vaccine by culturing autologous DCs infected with rAd-p53. This p53-DC vaccine can differentiate CTLs specifically cytotoxic to p53-overexpressing prostate cancer cells. In addition, rAd-p53 infection can induce overexpression of p53 and thus the cytotoxicity of CTLs differentiated by the p53-DC vaccine in p53 non-expressing prostate cancer cells. These findings suggest that this combination therapy using p53-DC vaccine and rAd-p53 gene therapy together may represent a new paradigm for the treatment of mCRPC.

Microstructural changes occurring in biomedical Co-Cr-Mo alloys with three carbon levels due to solution treatment and aging were investigated. Ingots of Co-Cr-Mo alloys with three different carbon levels were prepared by vacuum furnace melting; their chemical composition was Co-28Cr-6Mo-xC (x = 0.12, 0.25 and 0.35 mass%). Precipitates were electrolytically extracted from as-cast and heat-treated alloys. An M23C6 type carbide and a phase were detected as precipitates in as-cast Co-28Cr-6Mo-0.12C alloy, and an M23C6 type carbide and an  phase (M6C-M12C type carbide) were detected in as-cast Co-28Cr-6Mo-0.25C and Co-28Cr-6Mo-0.35C alloys. Only the M23C6 type carbide was detected during solution treatment. Complete precipitate dissolution occurred in all the three alloys after solution treatment. The holding time required for complete precipitate dissolution increased with increasing carbon content and decreasing solution treatment temperature. Complete precipitate dissolution occurred in the Co-Cr-Mo-C alloys solution treated at 1523 K for 43.2 ks; they were then subjected to aging from 873 to 1473 K for a heating time up to 44.1 ks after complete precipitate dissolution in solution treatment at 1523 K for 43.2 ks. The M23C6 type carbide with a grain size of 0.1–3 m was observed after aging. A time-temperature-precipitation diagram of the M23C6 type carbide formed in the Co-28Cr-6Mo-0.25C alloy was plotted.

A series of fluorosilicone (FLS) homopolymers with 4,4,5,5,6,6,7,7,8,8, 9,9,10,10,11,11,11-heptadecafluoroundecylmethylsiloxane [&bond;C8F17CH2CH2CH2(CH3) SiO&bond;; HDFUSiO] and copolymers based on dimethylsiloxane [&bond;(CH3)2SiO&bond;] were prepared by the hydrosilylation of 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-1-undecene (C8F17CH2CH&dbond;CH2) with poly(hydromethylsiloxane)s. Thermal characterization showed that the decomposition of fluoroalkyl side chains occurred at about 245 °C. Side-chain crystallization was observed for FLSs with more than 30 mol % HDFUSiO. The refractive index decreased with increasing HDFUSiO content. The dielectric constant increased with increasing HDFUSiO content. The liquid surface tension of the FLS containing 10 mol % HDFUSiO was as low as that of the highly fluorinated FLSs. FLSs with HDFUSiO and trichlorosilylethyl side chains (Cl3SiCH2CH2&bond;) were also prepared so that their solid surface tension (surface free energy) could be measured. The surface free energy of these FLSs decreased with increasing Cl3SiCH2CH2&bond; content, but the sliding angle of a water droplet and the contact-angle hysteresis adversely increased. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2704–2714, 2003

Recent studies have shown independently that presenilin-1 (PS1) null mutants and familial Alzheimer's disease (FAD)-linked mutants should both down-regulate signaling of the unfolded protein response (UPR). However, it is difficult to accept that both mutants possess the same effects on the UPR. Furthermore, contrary to these observations, neither loss of PS1 and PS2 function nor expression of FAD-linked PS1 mutants were reported to have a discernable impact on the UPR. Therefore, re-examination and detailed analyses are needed to clarify the relationship between PS1 function and UPR signaling. Here, we report that PS1/PS2 null and dominant negative PS1 mutants, which are mutated at aspartate residue 257 or 385, did not affect signaling of the UPR. In contrast, FAD-linked PS1 mutants were confirmed to disturb UPR signaling by inhibiting activation of both Ire1alpha and ATF6, both of which are endoplasmic reticulum (ER) stress transducers in the UPR. Furthermore, PS1 mutants also disturbed activation of PERK (PKR-like ER kinase), which plays a crucial role in inhibiting translation during ER stress. Taken together, these observations suggested that PS1 mutations could affect signaling pathways controlled by each of the respective ER-stress transducers, possibly through a gain-of-function.

When accumulation of a malfolded protein in the endoplastic reticulum (ER) is induced by various adverse conditions, such as hypoxia, glucose starvation, and perturbation of calcium homeostasis, cells respond to the stress by increasing transcription of genes encoding ER molecular chaperones, a process known as unfolded protein response. The signaling is initiated by IRE1s, ER stress sensors. Alternatively, excessive stress to the ER results in apoptosis. Caspase-12 is known to be essential for this ER stress-induced apoptosis. In this study, we analyzed the detailed regulatory mechanisms of IRE1s during ER stress. We identified c-Jun N-terminal inhibitory kinase (JIK) as a binding partner of IRE1alpha, and JIK was seen to modulate IRE1alpha-TRAF2 (tumor necrosis factor receptor-associated factor 2) complex formation and the resultant alteration to c-Jun N-terminal kinase signaling from IRE1s in response to ER stress. We also demonstrated that TRAF2 interacts with procaspase-12 and promotes the clustering of procaspase-12 and its activation by cleavage in response to ER stress. These results indicate that TRAF2 plays crucial roles not only in the signaling of the c-Jun N-terminal kinase pathway but also in activation of caspase-12 to transduce signals from IRE1s. Thus, we provide a missing link in the ER stress-induced apoptosis-signaling pathway, one which connects the stress sensor molecule IRE1 and the activation of caspase-12.

To elucidate the function of Bcl10, recently cloned as an apoptosis-associated gene mutated in MALT lymphoma, we identified its binding partner TRAF2, which mediates signaling via tumor necrosis factor receptors. In mammalian cells, low levels of Bcl10 expression promoted the binding of TRAF2 and c-IAPs. Conversely, excessive expression inhibited complex formation. Overexpressed Bcl10 reduced c-Jun N-terminal kinase activation and induced nuclear factor kappaB activation downstream of TRAF2. To determine whether overexpression of Bcl10 could perturb the regulation of apoptosis in vivo, we generated Bcl10 transgenic mice. In these transgenic mice, atrophy of the thymus and spleen was observed at postnatal stages. The morphological changes in these tissues were caused by acceleration of apoptosis in T cells and B cells. The phenotype of Bcl10 transgenic mice was similar to that of TRAF2-deficient mice reported previously, indicating that excessive expression of Bcl10 might deplete the TRAF2 function. In contrast, in the other organs such as the brain, where Bcl10 was expressed at high levels, no apoptosis was detected. The altered sensitivities to overexpressed Bcl10 may have been due to differences in signal responses to Bcl10 among cell types. Thus, Bcl10 was suggested to play crucial roles in the modulation of apoptosis associated with TRAF2.

Therapeutic effectiveness of bisphosphonates (BP) on bone metastases in patients with cancers including those of the breast and prostate has been well documented. However, there are still many important questions that remain unsolved or controversial. To obtain answers for these questions that are not readily addressed in a well-controlled manner in clinical studies, we have developed two animal models of bone metastasis (orthotopic and experimental). Using these models, we studied the effects of BP alone or in combination with anti-cancer agents on the metastasis of breast cancer to bone and visceral organs. In addition, we also determined the effects of BP on osteosclerotic metastases. We found that BP impaired the progression of bone metastases primarily through enhancing apoptosis in osteoclasts and breast cancer cells colonized in bone. In some situations, however, BP alone increased metastases in visceral organs including liver and adrenal glands. However, combination of BP with anti-cancer agents enhanced the suppression of tumour in both bone and visceral organs, leading to prolonged survival of tumour-bearing animals. Of potential importance, preventative administration of BP inhibited the development of eventual osteosclerotic bone metastases. These results suggest that BP exhibits diverse beneficial effects on osteolytic and osteoblastic bone metastasis and non-bone organ metastasis in breast cancer when administered appropriately. They also suggest that the animal models of bone metastasis described here allow us to produce clinically- relevant information that is useful for the design of optimal regimens of BP for the treatment of breast cancer patients with bone and visceral metastases.

The effect of surface orientations of supports on microstructures of MoS2clusters was investigated by high-resolution electron microscopy observations of Mo model catalysts supported on γ-Al2O3single crystal thin films with two kinds of surface orientations. By use of an electron beam evaporation method, epitaxial γ-Al2O3single crystal thin films with smooth surfaces were successfully grown on (111) and (100) MgAl2O4substrates. Mo model catalysts were prepared on these γ-Al2O3thin films by the vacuum evaporation method, using MoO3as a source material. After sulfidation at 773 K, relatively uniform basal bonded clusters were grown on (111) γ-Al2O3thin films. The particle size distribution was relatively narrow because of some cluster–support interaction. Their mean particle size was approximately 1.73 nm. On the other hand, edge bonded clusters were grown on (100) γ-Al2O3thin films. The mean cluster length was approximately 2 nm. From further discussions on the cluster–support interface at an atomic level, it seems reasonable to conclude that important factors for determining the orientation of MoS2clusters on γ-Al2O3supports could include similarities between the arrangement of Mo atoms in MoS2and the arrangement of Al or O atoms in γ-Al2O3surface.

Metastatic tumor cells can interfere directly with the function of bone cells involved in normal bone remodeling or indirectly by influencing the behavior of hematopoietic, stromal and other cells in bone marrow that interact with bone cells. Recent studies of metastatic cancer have revealed that tumor cells interact closely with vascular endothelial cells, basement membrane and bone marrow stromal cells through cell surface proteins or by releasing factors which affect the function of these cells. Bidirectional interaction between marrow cells and tumor cells can give the latter a selective advantage for growth in bone which can lead to the destruction of or to increased production of bone matrix. Understanding of the mechanisms involved in tumor metastasis and growth in bone has increased in recent years, and in this review we shall describe current knowledge of these mechanisms and of the predilection of certain types of cancers to metastasize to bone, their growth in the bone microenvironment and interactions between them and bone cells. Because metastatic breast cancer has been studied more than any other, we shall focus on it as a representative example, although the general principles apply to other types of cancer and to myeloma.

The distribution of a carbohydrate antigen, the sialyl SSEA-1 (sialyl Lex-i), in human lymphoid cells was investigated by flow cytometry with a specific monoclonal antibody, MoAb FH-6. We concluded that the lymphocytes positive for the sialyl SSEA-1 antigen present in normal peripheral blood (PB) are natural killer (NK) cells since the positive cells had an NK activity toward K562 cells, and most of the sialyl SSEA- 1+ cells were simultaneously positive for Leu-11 (CD-16) and Leu-19. Essentially, no T and B cells, defined by Leu-4 (CD3) and Leu-16 (CD20), were positive for the sialyl SSEA-1 antigen in PB samples taken from healthy donors and patients with disorders unrelated to lymphoid malignancies. Among the malignant lymphoid cells, many sialylated SSEA- 1+ cells were observed in large granular lymphocyte (LGL) leukemia cells and some acute lymphoblastic leukemia (ALL) blasts, but not in CLL cells or malignant lymphoma cells. Sialyl SSEA-1 was also positive in some cultured human lymphoid cell lines. We conclude that expression of the sialyl SSEA-1 antigen is strictly limited to a distinct population of NK cells among the mature lymphocytes in normal PB, but the antigen is present in a wide range of immature lymphoblasts of T- and B-cell lineages as well as the NK-cell lineage. The sialyl SSEA-1 antigen disappears from the surface of immature lymphocytes of T- and B- cell lineages during the course of maturation.

A temporary prosthesis has been developed for above-knee amputees who receive long-term post-amputation chemotherapy. The temporary prosthesis has an adjustable laminated quadrilateral socket, the size of which is adjusted by metal screws.Fifteen patients were fitted with the temporary prosthesis. Initial fittings were carried out after a period averaging 46 days from amputation. All of the patients were able to walk with one crutch after about one month from initial fitting. Although patients often had to discontinue their prosthetic training owing to chemotherapy, they could resume wearing their prostheses simply by adjusting the socket.One patient, who was fitted with a cosmetic ultra-light prosthesis initially due to her poor general condition, was later fitted with the temporary prosthesis. She regained the ability to walk 60 days later and still wears it.Early fitting of temporary prostheses for these patients is not only of practical convenience but also improves their mental state.

A temporary prosthesis has been developed for above-knee amputees who receive long-term post-amputation chemotherapy. The temporary prosthesis has an adjustable laminated quadrilateral socket, the size of which is adjusted by metal screws.Fifteen patients were fitted with the temporary prosthesis. Initial fittings were carried out after a period averaging 46 days from amputation. All of the patients were able to walk with one crutch after about one month from initial fitting. Although patients often had to discontinue their prosthetic training owing to chemotherapy, they could resume wearing their prostheses simply by adjusting the socket.One patient, who was fitted with a cosmetic ultra-light prosthesis initially due to her poor general condition, was later fitted with the temporary prosthesis. She regained the ability to walk 60 days later and still wears it.Early fitting of temporary prostheses for these patients is not only of practical convenience but also improves their mental state.

The clinical, biochemical and histopathological findings of an infantile disease occurring in the C3H-H-2° strain of mice, which has similarities with Reye's syndrome in children, is described.

To evaluate the significance of chromosomal aberrations in renal cell carcinoma, fluorescence in situ hybridization (FISH) was used to determine its prevalence and correlation with clinical parameters of malignancy. In addition, correlation of chromosomal aberration with Ki 67 expression was analysed. We performed FISH with chromosome-specific DNA probes, and the signal number of pericentromeric sequences on chromosomes 3, 7, 9 and 17 was detected within interphase nuclei in touch preparations from tumour specimen. The incidence of loss of chromosome 3 was significantly higher than those of chromosomes 7, 9 and 17 (P < 0.001, P = 0.03 and P < 0.001 respectively). Hyperdiploid aberration of chromosomes 3 and 17 was significantly correlated with tumour stage (P = 0.03, P = 0.02 respectively), whereas hyperdiploid aberration of chromosome 9 was associated with nuclear grade (P = 0.04). Disomy of chromosome 7 was correlated with venous involvement (P = 0.04). Ki 67 expression was significantly associated with hyperdiploid aberration of chromosome 17 (P = 0.01), but not with aberration of chromosome 3. There was a significant relationship between hyperdiploid aberration of chromosome 7 and Ki 67 expression (P = 0.01). In conclusions, gain of chromosome 17 may reflect tumour development, and aberration of chromosome 7 may affect metastatic potential of malignancy, whereas loss of chromosome 3 may be associated with early stage of tumour development in renal cell carcinoma.

Adhesion of cancer cells to vascular endothelium is an important step in haematogenous metastasis of cancer. A human hepatocellular carcinoma cell line, HepG2, strongly adheres to human umbilical vein endothelial cells (HUVECs) through the interaction of E-selectin and its carbohydrate ligand sialyl Lewis X. In this study, we investigated alteration in integrin expression on HepG2 cells, which follows the selectin-mediated initial adhesion of HepG2 cells to HUVECs. Expression of alpha2beta1 integrin was markedly increased when the HepG2 cells adhered to HUVECs. Among the tested cytokines that are known to be produced by endothelial cells, recombinant hepatocyte growth factor (rHGF) could replace the effect of HUVECs, and a similar increase in integrin expression was observed by the addition of 20 ng ml-1 rHGF to HepG2. The increment of alpha2beta1 integrin expression was significantly inhibited by anti-HGF neutralizing antibody treatment. HepG2 cells expressed alpha2, alpha6, beta1, and beta4 integrin subunits, but expression of integrins other than alpha2beta1 was not affected by the rHGF treatment. The rHGF treatment of HepG2 cells resulted in augmented adhesion to immobilized collagen. This augmentation in adhesion to collagen was completely blocked by the addition of anti-alpha2- or anti-beta1-integrin antibody. In double-chamber chemoinvasion experiments, transmigration of the HepG2 cells through extracellular matrix (ECM) gel was significantly accelerated by co-cultivation with HUVECs. A similar level of enhancement in transmigration activity of the cancer cells was observed by the addition of rHGF. Our interpretation of the results described above is that the cancer cells received stimulation from cytokines, such as HGF, presented by vascular endothelial cells, following the initial adhesion of cancer cells via selectins. This resulted in the secondary increment in the expression of cell adhesion molecules, such as the alpha2beta1 integrin, and led to the augmented adhesive activities of cancer cells towards extracellular matrices at vascular walls. We suggest that this sequence of events is involved in the facilitated migration of some cancer cells to extravascular tissues.

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Abstract: Chondrocytes were isolated from growth cartilage and resting cartilage of rat rib and cultivatedin vitro. The cultivated chondrocytes were placed in Millipore diffusion chambers, which were then implanted into the abdominal cavities of rats for several weeks and prepared for histological analysis. The results indicate that growth cartilage cells have a remarkable osteogenic potential, even after cultivationin vitro, whereas resting cartilage cells show no osteogenic activity. However, growth cartilage cells alone do not form new bone but require the participation of certain host cells to initiate osteogenic differentiation.

Gold particles containing plasma-polymerized styrene film were formed simultaneously by plasma polymerization and evaporation using an inductively coupled argon gas flow type reactor. Gold was used as the evaporated metal and styrene as the monomer. The plasma etching characteristics of the film were evaluated by O2 and CO2 plasmas using a reactor with parallel-plate electrodes. A structure of lines and spaces of 4µm width was successfully fabricated in the film on Si wafer by CO2 plasma etching through a mask pattern of plasma-polymerized resist. A self-developed pattern was obtained through the X-ray mask with polyimide substrate by synchrotron radiation. The molecular structure and atomic composition of the film were investigated by ESCA and TEM.

Since the bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) superfamily that induce the differentiation of mesenchymal precursor cells into the osteogenic cells, we identified the relevant signaling molecules responsible for mediating BMP-2 effects on mesenchymal precursor cells. BMP-2 induces osteoblastic differentiation of the pluripotent mesenchymal cell line C2C12 by increasing alkaline phosphatase activity and osteocalcin production. As recent studies have demonstrated that cytoplasmic Smad proteins are involved in TGF-beta superfamily signaling, we plan to isolate the relevant Smad family members involved in osteoblastic differentiation. We identified human Smad5, which is highly homologous to Smad1. BMP-2 caused serine phosphorylation of Smad5 as well as Smad1. In contrast, TGF-beta failed to cause serine phosphorylation of Smad1 and Smad5. We found Smad5 is directly activated by BMP type Ia or Ib receptors through physical association with these receptors. Following phosphorylation, Smad5 bound to DPC4, another Smad family member, and the complex was translocated to the nucleus. Overexpression of point-mutated Smad5 (G419S) or a C-terminal deletion mutant DPC4 (DPC4 delta C) blocked the induction of alkaline phosphatase activity, osteocalcin production, and Smad5-DPC4 signaling cascades upon BMP-2 treatment in C2C12 cells. These data suggest that activation of Smad5 and subsequent Smad5-DPC4 complex formation are key steps in the BMP signaling pathway, which mediates BMP-2-induced osteoblastic differentiation of the C2C12 mesenchymal cells.

Osteopetrosis is a bone modeling disorder resulting in excessive accumulation of bone matrix due to defective function of osteoclasts, the cells that resorb bone. Mice carrying a targeted disruption of the gene Src that encodes pp60c-src (Src), a nonreceptor protein tyrosine kinase, develop this phenotype but do not exhibit other overt defects despite the fact that the kinase is normally present in a broad variety of cell types. Because Src is expressed in osteoblasts as well as in osteoclasts and both are required for normal bone resorption, the basic defect could occur in either cell type. In this study we have used in vitro approaches and fetal liver transplantation into irradiated Src- recipients to demonstrate that the inherent defect is with osteoclasts and autonomous of the bone marrow microenvironment. This result (i) identifies a cell type in which Src function is essential and cannot be replaced by other related kinases and (ii) should allow the isolation of a substrate that is specific to Src.

Expression of two developmentally regulated carbohydrate antigens, the sialyl stage-specific embryonic antigen-1 (SSEA-1) and I-antigens, in human lymphocytes and lymphocytic leukemia cells was investigated using specific monoclonal antibodies. Sialyl SSEA-1 was expressed only on natural killer (NK) cells, and was essentially absent on resting mature T and B cells among normal peripheral lymphocytes. On the other hand, the I-antigen was strongly expressed on virtually all mature B cells, moderately expressed on most mature T cells, but not expressed on NK cells in normal donors. Expression of the two antigens on normal T and B cells was reversible; in vitro stimulation of normal lymphocytes with concanavalin A (Con A) resulted in the loss of I-antigen and appearance of sialyl SSEA-1 on CD3+ T blasts, whereas stimulation with pokeweed mitogen led to loss of I-antigen expression and appearance of sialyl SSEA-1 antigen on CD19+ B blasts. Among lymphocytic leukemia cells, sialyl SSEA-1 was detected primarily on leukemia cells having immature properties such as most common acute lymphocytic leukemia (cALL) blasts, while the I-antigen was frequently expressed on malignant cells having relatively mature properties, such as those found in adult T- cell leukemia or chronic lymphocytic leukemia, and only occasionally on cALL blasts. Among normal peripheral lymphocytes, the sialyl SSEA-1+I- antigen- NK cells selectively underwent E-selectin (ELAM-1, endothelial- leukocyte adhesion molecule-1)-dependent adhesion to endothelial cells, while the I-antigen+sialyl SSEA-1- mature T and B cells did not, in line with the recent finding that sialyl SSEA-1 serves as a specific ligand for E-selectin. Con A blasts, which are sialyl SSEA-1+I-antigen- , also exhibited significant E-selectin-dependent adhesion to endothelial cells. These results indicate that expression of the sialyl SSEA-1 and I-antigens varies alternately depending on the differentiation/activation status of the lymphocytes, and that this at least partly regulates the behavior of lymphocytes at the vessel wall.

Osteoclast-activating factor (OAF), a powerful stimulator of osteoclastic bone resorption, is released by peripheral blood mononuclear cells on exposure to phytohemagglutinin (PHA) or a specific antigen to which the leukocytes have been previously exposed. Both lymphocytes and monocytes are required in the leukocyte population for OAF release to occur. In this study we examined the relationship between the lymphocyte and monocyte in OAF production. Biological activity, as a result of OAF, was assessed by a bioassay based on the release of previously incorporated 45Ca from fetal rodent long bones in organ culture. We found that an enriched lymphocyte population depleted of monocytes by serial adherence does not release OAF after stimulation with PHA, although the cells are activated as assessed by [3H]thymidine and 3H-amino acid incorporation. When conditioned media harvested from adherent cells which did not contain OAF was added to the enriched lymphocytes, OAF release occurred. Media harvested from adherent cells which were cultured with indomethacin (10 microM), an inhibitor of prostaglandin synthesis, did not permit OAF release by activated lymphocytes. When PGE1 and PGE2 (0.1 microM) were added exogenously to the enriched lymphocyte population, OAF release occurred after stimulation with PHA. These results indicate that, (a) the activated lymphocyte is the cell or origin of OAF, (b) prostaglandins produced by monocytes are necessary for OAF production by activated lymphocytes, and (c) monocyte prostaglandins can influence bone resorption indirectly by regulating OAF production as well as directly by osteoclast activation. The interactions of OAF and prostaglandins at bone resorbing sites may be important in inflammatory and neoplastic diseases associated with bone destruction.