PubMed Health⌕ Search

Biomedical subjects

D R Clohisy

Publications and source records attributed to D R Clohisy.

34 records · Page 2Linked to original sources
PubMed1998

Osteoclasts are required for bone tumors to grow and destroy bone.

It has been hypothesized that bone resorption during tumor osteolysis is performed by osteoclasts. Data supporting this hypothesis have been provided from analysis of human biopsy specimens obtained from sites of tumor osteolysis, as well as from experimentation with in vivo animal models. Experiments in this report take this concept one step further by testing the hypothesis that osteoclasts are required for bone tumors to grow and destroy bone. To test this hypothesis, the influence of an osteolytic sarcoma tumor, NCTC clone 2472 (2472), on bone was studied in animals that are osteoclast deficient (microphthalmic, strain B6C3Fe-a/a-Mitf(mi)) but whose osteoclast deficiency can be reversed following bone marrow transplantation. Femora of these mice and unaffected wild-type siblings were injected with 10(5) 2472 cells, and after 14 days the femora were analyzed by radiographic and histomorphometric analysis. Macroscopic tumor, tumor-induced osteolysis, and increased osteoclast number were noted in femora of normal mice but not in femora of osteoclast-deficient mice (p < 0.001). Bone marrow transplantation converted osteoclast-deficient mice to mice with femora that contained osteoclasts in 4 weeks. Femora of these mice were then injected with 10(5) 2472 tumor cells; after 14 days, in contrast to the findings in the original osteoclast-deficient mice, macroscopic tumor was present, tumor-induced osteolysis was noted on roentgenograms, and osteoclast number was increased when tumor-bearing limbs were compared with sham-injected limbs (p < 0.001). These data prove the hypothesis that osteoclasts are required for 2472 tumor-induced osteolysis, and they introduce the exciting possibility that osteoclasts are also required for tumors to grow in bone.

Animals↗
PubMed1997

Osteoclast formation during tumor osteolysis does not require proliferating osteoclast precursor cells.

The cellular mechanism or mechanisms through which tumors induce osteoclast formation at sites of tumor osteolysis is unknown. To test the hypothesis that osteoclast formation at sites of tumor osteolysis reflects influences that tumors have on proliferating osteoclast precursor cells, a novel in vivo experimental model was developed that produced mice that were deficient in osteoclasts (op/op) and were depleted (by way of total body irradiation) of proliferating osteoclast precursor cells. The femora of irradiated op/op mice were injected with tumor cells (2472 clone) that had been previously shown to form osteolytic tumors and to induce focal osteoclastogenesis, and the influence of these tumor cells on osteoclast formation was determined in op/op mice that were depleted of proliferating osteoclast precursor cells. The results indicated that 2472 tumor cells induced osteoclast formation in op/op mice despite the absence of proliferating osteoclast precursor cells. This finding disproved the hypothesis under investigation and suggests that osteoclast formation at sites of tumor osteolysis reflects influences of tumors on postmitotic, not proliferating, osteoclast precursor cells.

Animals↗
PubMed1997

Measuring health status in patients with skeletal metastases treated by surgery.

Since the introduction of the Functional Living Index-Cancer (FLIC) > 10 years ago, a variety of general as well as disease-specific quality of life (QOL) instruments have been developed and used as a means of assessing the success of clinical interventions. Clinicians faced with selecting an appropriate QOL measurement tool will need guidance in both the selection of the instrument and its evaluation for applicability to the patient group under study. In our examination of this issue, we analyzed the results of administering the FLIC and the more general SF-36 questionnaire to a group of 17 patients who had undergone orthopaedic surgery to correct problems associated with bone metastatic cancer. Because the SF-36 has been widely adopted as a general Health Status evaluation tool and because of its extensive validation it may be considered a gold standard providing a means of assessing the validity of disease-specific instruments such as the FLIC. Using multivariate regression, we built a model in which five of the eight health status dimensions of the SF-36 account for 77% of the variation in the FLIC scores for this group of patients (R2 = 0.77). The implication of this result is that most of the information (i.e., 77%) provided by the FLIC could be equivalently obtained using the more general, more widely validated SF-36. Despite the small sample size, half of the regression coefficients in this model achieved a high level of statistical significance (p < 0.001). In addition, when applied to new patients, the model showed good predictive capability with relative error 2-20%. If these results can be replicated for other patient disease groups and in larger study populations, it may be possible to use the SF-36 as the primary QOL evaluation tool for cancer patients. The burden of this disease could then be more easily compared with that of other disease groups and the resulting standardization of QOL analysis would be simpler and more cost effective.

Aged↗
PubMed1996

Localized, tumor-associated osteolysis involves the recruitment and activation of osteoclasts.

The cellular and biochemical mechanisms that direct destruction of bone at the site of tumor osteolysis are unknown. In order to understand this process better, a murine model designed for the study of tumor osteolysis was developed and the influence of osteolytic and nonosteolytic tumors on bone was investigated. Tumors developed following femoral intramedullary injection of sarcoma (2472) and melanoma (G3.26) cell lines; however, only tumors from the 2472 cell line caused osteolysis. It was determined that 2472 tumor-induced osteolysis commenced 6 days after the femora had been inoculated with 2472 cells. There were more osteoclasts per millimeter of bone surface in 2472 tumor-bearing limbs (16.7 +/- 5.0) than in sham-injected limbs (3.8 +/- 0.9) (p < 0.015). In addition, an increase in the osteoclast size (area) was detected in 2472 tumor-bearing limbs: 412 +/- 65 micron2 compared with 187 +/- 17 micron2 (p < 0.01). In vitro bone resorption experiments indicated that 2472 tumor cells had a limited ability to destroy bone in comparison with macrophages and osteoclasts. Taken in total, these findings define a model that is useful for the study of tumor osteolysis, and the data from analyses of the model demonstrate that the cellular mechanisms responsible for 2472 tumor-induced osteolysis include both an increase in the number of osteoclasts and activation of mature osteoclasts.

Animals↗
PubMed1996

Human breast cancer induces osteoclast activation and increases the number of osteoclasts at sites of tumor osteolysis.

The cellular mechanism through which osseous breast cancer metastases induce the focal destruction of bone (tumor osteolysis) is unknown. An athymic mouse model designed for the study of tumor osteolysis was developed and the influence of two human breast cancer tumors on bone was studied. Tumor-induced osteolysis occurred between 7 and 10 weeks after inoculation of mouse femora with MDA-MB-231 or MDA-MB-435s breast cancer cells. An increase in osteoclast number and an increase in osteoclast size (area) were detected when tumor-bearing and sham-injected limbs were compared. In vitro analysis of the influence of the tumor-conditioned medium on osteoclast-mediated bone resorption revealed that this conditioned medium stimulated the resorption by increasing both the number of osteoclasts bound to bone and the number of bone resorption pits formed per osteoclast. In addition, in vitro analysis of the influence of breast cancer tumor cells on osteoclast formation or survival, or both, demonstrated that breast cancer cells induced a dramatic increase in the number of osteoclasts detected in culture. Taken in total these findings suggest that human breast cancer tumors induce osteolysis by enhancing osteoclast adherence to bone, stimulating osteoclast-mediated bone resorption and either prolonging the survival of osteoclasts or increasing osteoclast formation.

Animals↗
PubMed1995

Tumor osteolysis in osteopetrotic mice.

Details of the cellular and biochemical mechanisms involved in focal destruction of bone at sites of tumor osteolysis are unknown. It has been shown that tumors from sarcoma (2472) cell lines induce focal osteolysis in mice by stimulating formation and activation of osteoclasts. In this report, the influence of 2472 tumors on the skeletons of osteoclast-deficient animals (op/op) was studied. After op/op femora had been inoculated with 2472 cells, tumors developed and focal osteolysis occurred. There were more osteoclasts per histologic section in sham-injected femora (19 +/- 5) than in tumor-bearing femora (412 +/- 129) (p < 0.05). The size of the osteoclasts also increased from 304 +/- 81 microns 2 in sham-injected limbs to 407 +/- 62 microns 2 in tumor-bearing limbs (p < 0.001). Conditioned media from 2472 op/op tumor explants contained macrophage colony-stimulating factor. A deficiency of osteoclasts in op/op mice is the result of the absence of this factor; therefore, these data introduce the possibility that macrophage colony-stimulating factor derived from 2472 tumor may be responsible for directing osteoclast-mediated osteolysis at sites of the tumor.

Animals↗
PubMed1994

Osteoarticular allografts for reconstruction after resection of a musculoskeletal tumor in the proximal end of the tibia.

An osteoarticular allograft was used to reconstruct a skeletal deficiency in sixteen patients after resection of a tumor in the proximal end of the tibia. The status of each allograft and the condition of each involved limb were evaluated an average of nine years (range, six to fourteen years) postoperatively. The status of the allograft was evaluated according to the survival of the allograft and the occurrence of complications. Of the original sixteen allografts, seven were removed: six, between two and five years after the reconstruction and one, seven years after the reconstruction. A second reconstruction with use of an allograft was performed in five of the seven patients. Fifteen complications occurred in association with eleven of the original sixteen allografts. These included fracture of the allograft (five patients), subchondral collapse (five patients), infection (two patients), non-union (two patients), and instability of the joint (one patient). At the latest follow-up examination, nine patients had retained the original allograft, five had had a second allograft procedure, and two had had an above-the-knee amputation. The most recent result was rated excellent or good in eleven patients and fair or a failure in five, with use of the system of Mankin et al. It was rated good or excellent in nine patients and fair, poor, or a failure in six, and it was not rated in one patient who had died, according to the system of the Musculoskeletal Tumor Society.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Deformity following fracture in diabetic neuropathic osteoarthropathy. Operative management of adults who have type-I diabetes.

We studied fifteen lower extremities that had a deformity following a fracture in the region of the ankle or the tarsal bones, in fourteen adults who had type-I diabetes and neuropathic osteoarthropathy. The skeletal deformities associated with these fractures were either diagnosed late (two limbs) or occurred in lower extremities that had been treated by means other than non-weight-bearing and immobilization (thirteen limbs). All deformities were severe and secondary to a non-union or malunion of the fracture; all were ultimately treated with operative reconstruction. Before the reconstruction, the limbs had had either persistent ulceration associated with an uncorrectable skeletal deformity (four) or a severe deformity that was difficult to contain with a custom-made orthosis (eleven). The most recent result was considered a success when the ulceration had healed, the involved foot was planti-grade, and the involved limb was capable of bearing weight with use of a patellar tendon-bearing orthosis. Following reconstruction, ten patients had a plantigrade foot without ulceration, three had a plantigrade foot with a persistent draining ulcer, and one had a foot that was not plantigrade. In the limbs that had an ulcer at the time of the operation, there was one successful outcome and three failures. In contrast, the outcome was successful for ten of the limbs that had not had an ulcer and a failure for one. There were three complications following sixteen operative reconstructive procedures in the fourteen patients, including one infection and two instances of accelerated bone resorption and collapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Histochemical and immunohistochemical characterization of cells constituting the giant cell tumor of bone.

Enzymatic activity and cell membrane proteins were characterized in cells from five giant cell tumors of bone (GCTs). Naphthyl alpha esterase (NAE) and acid phosphatase (AP) activity was noted within both the mononuclear and multinucleated cells of each tumor. In each tumor, all mononucleated cell populations displayed tartrate-sensitive AP activity, whereas the multinucleated cell populations demonstrated variable expression of tartrate-sensitive and tartrate-resistant AP activity. Analysis of cell membrane proteins included attempts at immunodetection of mannose receptor, OKM-1 antigen (OKM-1a), colony-stimulating factor-1 receptor (CSF-1r), and platelet-derived growth factor receptor (PDGFr). None of these membrane antigens were elicited on multinucleated cells. In contrast, the mannose receptor, OKM-1a, and PDGFr all were detected on the mononucleated cells within each tumor. These data demonstrate that a population of mononucleated, not multinucleated cells, expresses features unique to mature mononuclear phagocytes and establishes the presence of a membrane receptor, PDGFr, associated with mitogenesis of mesenchymal cells.

Acid Phosphatase↗
PubMed1990

Thrombin binds to murine bone marrow-derived macrophages and enhances colony-stimulating factor-1-driven mitogenesis.

The binding and mitogenic properties of thrombin have been established in various transformed cell lines. In such systems, thrombin induces cell division in the absence of exogenous growth factors, and the enzyme is considered to act directly as a mitogen. This study explores thrombin's interaction with nontransformed, growth factor-dependent cells. Binding of 125I-alpha-thrombin to colony-stimulating factor (CSF)-1-dependent bone marrow-derived macrophages is saturable, time-dependent, and displaceable by both unlabeled alpha-thrombin, and esterolytically inactive thrombin. Both dissociation studies of pre-bound radio-labeled thrombin and Scatchard analysis assisted by the program "Ligand" suggest adherence of thrombin-binding data to a multi-site model. There are an estimated 2 x 10(4) high affinity sites (Kd = 7 x 10(-9)M) and 2 x 10(6) low affinity sites (Kd = 9 x 10(-7)M) per cell. Quiescent bone marrow-derived macrophages were cultured with either 10(-8)M thrombin, 1000 units of CSF-1/ml, or both and [3H]thymidine incorporation was determined. Thrombin alone did not induce mitogenesis. CSF-1 induced mitogenesis with peak [3H] thymidine incorporation occurring 24 h after addition of the mitogen. This CSF-1-dependent mitogenic influence was enhanced greater than 2-fold by treatment with thrombin.

Animals↗
PubMed1989

Bone marrow-derived mononuclear phagocytes autoregulate mannose receptor expression.

This study extends our previous observation that surface mannose receptor expression by pure populations of CSF-1-dependent bone marrow-derived macrophages increases with time (Clohisy, D. R., Bar-Shavit, Z., Chappel, J. C., and Teitelbaum, S. L. (1987) J. Biol. Chem. 262, 15922-15929). We presently find, however, that the progressive enhancement of 125I-mannose-bovine serum albumin (125I-Man-BSA) binding per cell reflects cell number rather than duration of culture. In fact, macrophages plated at high density bind 8-fold more 125I-Man-BSA than do their low density counterparts, with no difference in receptor-ligand affinity. Furthermore, cells cultured at high density are ultimately subjected to lower levels of exogenously provided macrophage growth factor, and fewer are in interphase. By obtaining synchronous populations of quiescent bone marrow macrophages, however, we demonstrate that neither cell cycling nor attendant levels of colony stimulating factor-1 influence mannose receptor expression. Our next series of experiments established that density-related mannose receptor expression reflects removal, by marrow macrophages, of a "down-regulating" factor contained in culture medium. To this end, we treated mononuclear phagocytes with either macrophage- or control-conditioned medium and found that, via a fetal calf serum-residing protein(s), only control medium is capable of noncompetitively reducing 125I-Man-BSA binding in a dose-dependent manner. Moreover, reconstituted 20-40% (NH4)2SO4-precipitable fractions derived from either sham-conditioned medium or fetal calf serum are capable of down-regulating mannose receptor expression. Alternatively, the same fraction obtained from macrophage-conditioned medium contains no such activity. Finally, initial characterization of the down-regulating factor reveals it to be acid-activable and trypsin-sensitive, yet resistant to heating to at least 80 degrees C, ribonuclease A, or freezing and thawing. We conclude that bone marrow macrophages up-regulate expression of their own plasma membrane mannose receptor by inactivating a noncompetitive, serum-residing inhibitory protein(s).

Animals↗
PubMed1988

Fractures associated with neuropathic arthropathy in adults who have juvenile-onset diabetes.

Eighteen patients, twenty-five to fifty-two years old, who had juvenile-onset diabetes, had neuropathic arthropathy and fractures at the ankle or tarsus, most of which were bilateral. After a minimum follow-up of one year, four patients could not walk and fourteen were dependent on orthoses. In nine patients, the lesions produced fixed skeletal deformities that caused severe malum perforans, which in three patients was so severe that a below-the-knee amputation had to be done. In patients who had bilateral lesions, when the extremity that was initially involved was prevented from bearing weight, involvement of the contralateral limb became evident after an average of 4.5 months, compared with an average of twelve months in the patients who were allowed weight-bearing on the extremity that was initially involved. Our current treatment protocol is non-weight-bearing immobilization of the involved extremity, and we recommend prophylactic immobilization of the contralateral extremity with a protective cast or orthosis. All of the patients who had this treatment regimen could walk; in contrast, of the eleven patients who were not so treated, four could not walk.

Adult↗
PubMed1987

1,25-Dihydroxyvitamin D3 modulates bone marrow macrophage precursor proliferation and differentiation. Up-regulation of the mannose receptor.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the biologically active form of vitamin D3, has been shown to inhibit proliferation and promote monocytic differentiation of leukemic cell lines. In the present communication, we extend these observations to normal bone marrow macrophage precursors, and 1) identify the stage of monocytic maturation wherein the steroid exerts its antiproliferative effect, and 2) demonstrate that 1,25-(OH)2D3 promotes bone marrow macrophage differentiation as manifest by specific up-regulation of the lineage-specific membrane protein, the mannose-fucose receptor. In these experiments, the 1,25-(OH)2D3-mediated inhibitory effect on colony formation was shown to be independent of attendant levels of colony stimulating factor-1 and targeted through the adherent bone marrow macrophage precursor. Examination of this steroid-sensitive adherent precursor population demonstrates that its specific binding of 125I-mannose bovine serum albumin spontaneously and progressively increases with time in culture. Whereas adherent bone marrow macrophages cultured for 2 days express 3 X 10(4) mannose receptors/cell, the number of binding sites increases to 7 X 10(4)/cell by day 4. When bone marrow macrophage precursors are exposed to 1,25-(OH)2D3, an additional stepwise enhancement of 125I-mannose bovine serum albumin obtains with time. Four days of culture with the steroid results in 1.6 X 10(5) mannose receptors/cell, a 100% increase as compared to control cells. Neither duration of culture nor exposure to 1,25-(OH)2D3 alters the KD of 125I-mannose bovine serum albumin which approximates 3-5 X 10(-9) ml-1. Finally, the "specificity" of vitamin D-mediated up-regulation of the mannose receptor was established by demonstrating that the steroid does not alter binding of 125I-alpha-thrombin by bone marrow-derived macrophage precursors.

Animals↗
PubMed1982

Effect of quinidine on the renal clearance of digoxin in the presence of low and high serum digoxin concentrations.

The effect of an infusion of quinidine, 180 micrograms/kg/Min (base) on the fractional clearance of digoxin (CDIG/Cin) was studied in saline volume-expanded dogs given a constant infusion of digoxin of either 0.0067 micrograms/kg/min (low dose) or 0.120 micrograms/kg/min (high dose). CDIG/CIN decreased 28% from 1.42 +/- 0.36 during control periods to 1.01 +/- 0.03 (P less than .05) with quinidine in dogs given the low dose. In dogs given the high dose of digoxin, CDIG/CIN decreased 22% from 0.76 +/- 0.17 to 0.59 +/- 0.05 (p less than .05) with quinidine. It is concluded that quinidine reduces CDIG/CIN. High doses of digoxin also reduce CDIG/CIN. Inasmuch as quinidine reduces CDIG/CIN to the same extent in the presence of low or high dose digoxin, the effect of quinidine would appear to be mediated through a mechanism different from that of digoxin.

Animals↗
PubMedDate not supplied

Comparison of pharmacokinetic parameters of intravenous quinidine and quinine in dogs.

The pharmacokinetic parameters of quinidine and quinine were determined and compared in seven mongrel dogs. Both drugs were given intravenously, with a minimum of 4 weeks between protocols, and blood samples collected for 20-24 h. Depending on the distribution phase, both two- and three-compartment models were used to describe the kinetics. The volumes of distribution, intercompartmental clearance rates, and volumes of the central and peripheral compartments were similar. The total body clearance (ClT) of quinidine, 3.58 +/- 1.96 (SD) ml/kg/min, was 56% slower than that of quinine, 8.11 +/- 3.03 ml/kg/min, with p less than 0.02. Quinine half-life (t1/2), 6.58 +/- 3.3 h, was 54% less than that of quinidine, 14.4 +/- 4.10 h, p less than 0.02.

Animals↗