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PubMed1997

Merocyanine 540 mediated photolysis of normal bone marrow, committed hemopoietic progenitors and neoplastic cells. implications for bone marrow purging.

The effect of merocyanine 540 (Mc 540) mediated photoirradiation on both neoplastic and normal hemopoietic progenitor cells was studied. Bone marrow (BM) cells from children with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) at initial diagnosis, ALL in remission, neuroblastoma and normal children as well as cells of Reh-6 and HL-60 cell lines were incubated with Mc 540 in the presence of human albumin (HA) and exposed to different argon laser 514 nm doses. Cell survival was estimated using Trypan Blue supravital stain following a 24-h incubation and leukemic cell lines were studied in continuous cell cultures of 4 weeks duration. Our results showed that HA protects normal BM cells from Mc 540 mediated phototoxicity. A 99.9999% inhibition of Reh-6 and HL-60 was noted at irradiation doses where the corresponding mean survival of normal BM cells was 77.4 +/- 12 and 70.3 +/- 10%, respectively. BM leukemic cells from children with ALL and AML were also very sensitive to Mc 540 photoirradiation in contrast to neuroblastoma cells where only a three-fold reduction was observed. Finally, the survival of normal BM progenitors was 38% for colony forming unit erythroid CFU-E, 37% for burst forming unit erythroid BFU-E, 55% for CFU-GM and 29% for CFU-GEMM. In conclusion it seems that Mc 540 mediated photoirradiation in neoplastic cells exerts selective cytotoxicity and can be used in ex vivo purging of malignant cells in BM.

Bone Marrow↗
PubMed2006

Co-transplantation of bone marrow stromal cells transduced with IL-7 gene enhances immune reconstitution after allogeneic bone marrow transplantation in mice.

Allogeneic bone marrow transplantation (allo-BMT) is followed by a period of profound immune deficiency, which results in significant susceptibility to infections and limits the extensive application of this approach in clinic. Here, we transduced human interleukin-7 (IL-7) gene into donor-derived bone marrow stromal cells (MSCs) using adenovirus vector, and transplanted this gene-engineered MSCs (MSC-IL-7) into lethally irradiated C57BL/6 mice to investigate their effects on immune reconstitution following allo-BMT. Recipient mice receiving MSC-IL-7 cells plus T-cell-depleted bone marrow cells of BALB/c mice showed a significant increase in thymopoiesis and homeostatic expansion of peripheral T lymphocytes. Furthermore, injection of MSC-IL-7 cells following allo-BMT protected the host from the lethality caused by acute graft-versus-host disease (GVHD) and prevented the occurrence of GVHD induced by transplanted T cells. Thus, the use of MSC-IL-7 cells may be therapeutically useful for enhancing immune reconstitution without aggravating GVHD in allo-BMT mice.

Adenoviridae↗
PubMed2001

Allogeneic bone marrow transplantation in children failing prior autologous bone marrow transplantation.

Twenty-three children with de novo acute myelogenous leukemia (AML) (n = 20), secondary AML (n = 1), or non-Hodgkin's lymphoma (NHL) (n = 2) underwent allogeneic bone marrow transplantation (alloBMT) for graft failure (n = 1) or recurrent malignancy (n = 22) between February 1992 and August 1999 following autologous BMT (ABMT). Induction chemotherapy was given to 14 patients and nine patients went directly to alloBMT. Five received marrow from matched siblings, 14 from matched unrelated donors and four from mismatched family members. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Nine patients are alive disease-free between 627 and 2433 days (1.7-6.7 years) post BMT resulting in a 4-year DFS of 39%. Eight patients relapsed at a median of 206 days (range, 35-669 days) post alloBMT and all eventually died. Eight patients (two of whom also relapsed) died of RRT. Although RRT and relapse remain significant problems, a significant percentage of pediatric patients failing ABMT may be cured with alloBMT.

Adolescent↗
PubMed1990

Autologous bone marrow transplantation for acute myeloid leukemia using monoclonal antibody-purged bone marrow.

We report our experience from a clinical trial of autologous bone marrow transplantation (ABMT) in the treatment of 30 patients with acute myeloid leukemia (AML) using monoclonal antibody (MoAb) and complement-treated bone marrow. All patients were in complete remission (CR) at the time of transplant: 6 patients were in first CR, 18 in second CR, and 6 in third CR. The median age of all patients was 42 years (range 11 to 57 years). For marrow ablation, 28 patients were treated with cyclophosphamide and total body irradiation. One patient was treated with busulfan and cyclophosphamide and one was treated with busulfan and VP-16. Each patient was then transfused with autologous bone marrow that had been harvested previously and treated with two MoAbs, PM-81 and AML-2-23, and rabbit complement. Median time to recovery of neutrophils (500/microL) was 30 days, and platelets (20,000/microL) was 45 days. Median time for initial erythrocyte engraftment, assessed by a flow cytometric reticulocyte assay, was 13 days. Median overall and relapse-free survival of first CR patients was at least 17.4 months post-ABMT and the 2- and 3-year actuarial overall and relapse-free survival was 67% (+/- 19%). Median survival for the 24 patients in second or third CR was 6.8 months post-ABMT and 9.3 months since CR; however, six patients survived disease-free from 16 to 61 months post-ABMT. For the second and third CR group it was observed that six patients (5 of the 6 survivors) showed "inversions," when their post-ABMT remission lasted longer than any previous one. Actuarial 2- and 3-year disease-free and overall survival of patients in second and third CR was 25% (+/- 9%) and 18% (+/- 9%), and 29% (+/- 9%) and 23% (+/- 9%), respectively. ABMT avoids the problems of graft-versus-host disease and of finding suitable donors for allogeneic marrow transplantation.

Adolescent↗
PubMed1994

Bone marrow transplantation in the People's Republic of China. Chinese Bone Marrow Transplant Registry.

Bone marrow transplantation, both allogeneic and autologous, has been undertaken in People's Republic of China (PRC) since the beginning of 1980s at a steadily increasing rate. Eight BMT units can be regarded as active. Altogether 230 cases of allogeneic- and syngeneic-BMT have been reported to the Chinese BMT Registry (CBMTR) by the end of October 1993. More than 85% of the cases were acute or chronic leukemia. The incidence of acute grade II-IV GVHD was 29.5% in matched sibling BMT. The special problems of BMT in China include decreasing family size, financial difficulties and relatively high incidence of various viral infections. A number of unique approaches to treatment have been tested with benefit including mixed infusion of fetal cells for prophylaxis of acute GVHD and intravenous placental globulin for the treatment of chronic GVHD. Garlic ingredient has been shown to be effective against CMV and has been used in the clinic with encouraging results. The overall outcome of allogeneic and autologous BMT are comparable to those in the other major BMT centers in the world.

Bone Marrow Transplantation↗
PubMed2000

Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the international bone marrow transplant registry.

Allogeneic bone marrow transplantation (BMT) is the only curative therapy for chronic myelogenous leukemia (CML), though several studies indicate that prolonged survival can result from interferon-alpha (IFN-alpha) treatment. IFN-alpha is now often used as initial therapy for CML, before donor availability is known. Because identifying potential donors can take several weeks to months, it is important to know whether IFN-alpha adversely affects outcome of a subsequent BMT. If it does, initiation of IFN-alpha therapy might be delayed until donor availability is determined and avoided in patients for whom BMT is planned. We studied 873 patients who received HLA-identical sibling BMT for chronic-phase CML in 153 centers participating in the International Bone Marrow Transplant Registry. The object was to compare outcome in the 664 who received only hydroxyurea before BMT with outcome in the 209 who received IFN-alpha with or without hydroxyurea. The median duration of IFN-alpha therapy was 2 months (range, 1 to 39 months). Cox proportional hazards analysis was used to compare engraftment, graft-versus-host disease (GVHD), nonrelapse mortality, relapse, survival, and leukemia-free survival after adjustment for other prognostic variables. We found a higher risk of nonengraftment among patients given IFN-alpha than among those given hydroxyurea alone (2% versus 0.2%; P = 0.01). Patients who received IFN-alpha had a lower risk of relapse (relative risk, 0.17; 95% confidence interval, 0.04-0.70). Probabilities of GVHD, nonrelapse mortality, survival, and leukemia-free survival were similar in the two treatment groups. These results suggest that a short course of IFN-alpha does not adversely affect survival after a subsequent HLA-identical sibling BMT for chronic-phase CML. (Blood. 2000;95:410-415)

Actuarial Analysis↗
PubMed1996

High dose therapy and autologous bone marrow versus blood cell rescue. South Island Bone Marrow Transplant Unit.

AIMS: To compare haematological recovery and supportive care requirements for patients receiving high dose therapy (HDT) supported by rescue with either autologous cytokine mobilised blood cells (BC) or autologous bone marrow (BM). To identify stem cell harvest criteria predictive of rapid haematological recovery after rescue with BC. METHODS: Single arm, open study in four groups of 69 consecutive patients undergoing HDT in a single institution from 1986-95. Group 1 contained patients with solid tumours or myeloma rescued with BC alone (n = 14); group 2 patients with solid tumours rescued with BM (n = 31); group 3 patients with acute leukaemia rescued with BM (n = 21); and group 4 patients with solid tumours rescued with both BC and BM (n = 3). RESULTS: Haemopoietic recovery was most rapid for group 1 where, in comparison with the BM group transplanted for similar disease (group 2), highly significant reductions were observed for median days to 1) neutrophil s >/= 0.5 x 10(9)L (12 v 22; p 0.0001); 2) neutrophils >/= 1.0 x 10(9)/L (14 v 27 ; p = 0.0001); platelets >/= 20 x 10(9) /L (11 v 20; p = 0.0005); and 4) platelets >/= 50 x 10(9)/L (15 v 27; p = 0.001). Similar significant reductions for the BC group over group 2 were also observed for median, (1) inpatient days (22 v 30; p = 0.0001); (2) red cell transfusions (2 v 5; p = 0.01) ; (3) platelet transfusions (2 v 6; p = 0.0001); (4) days of fever (2 v 8; p = 0.001); and (5) days on IV antibiotics (8 v 14; p = 0.02). Group 3 patients yielded data either similar to or less advantageous to that in group 2 and group 4 patients yielded data intermediate between groups 1 and 2. Data from BC harvests suggested that yields of CD34+ cells of > 2.0 x 10(6)/kg and/or of colony forming units-granulocyte-macrophage (CFU-GM) of > 6.0 x 10(4)/kg were predictive of rapid haemopoietic recovery. CONCLUSION: For haemopoietic rescue following single HDT for solid tumours BC has considerable advantages over BM.

Adolescent↗
PubMedDate not supplied

A preliminary comparative study of radiographic results using mineralized collagen and bone marrow aspirate versus autologous bone in the same patients undergoing posterior lumbar interbody fusion with instrumented posterolateral lumbar fusion.

BACKGROUND CONTEXT: Multiple bone graft substitutes for spinal fusion have been studied with varying results. PURPOSE: The purpose of this study was to assess the effectiveness of a mineralized collagen matrix combined with bone marrow, versus autologous bone, in the same patients undergoing a posterior lumbar interbody fusion and an instrumented posterolateral lumbar fusion. STUDY DESIGN/SETTING: A prospective, comparative study. PATIENT SAMPLE: Patients indicated for one-level posterior lumbar interbody fusion and instrumented posterolateral lumbar fusion, serving as self-controls. OUTCOME MEASURES: Thin-cut computed tomographic scans with sagittal reconstruction and plain radiographs, including lateral flexion/extension views were performed and assessed at 12 and 24 months after surgery. Oswestry Disability Index and Visual Analog Scale questionnaires were completed by all patients preoperatively and at 12 and 24 months after surgery. METHODS: After informed consent and failure of nonoperative treatment, 25 consecutive patients requiring one-level instrumented posterolateral fusion combined with posterior interbody fusion were enrolled in the study. Mineralized collagen bone graft substitute combined with bone marrow aspirate was used on one side of the posterolateral fusion, with iliac crest autograft on the contralateral side. RESULTS: A fusion rate of 84% (21/25) was achieved for the autologous bone grafts and 80% (20/25) for the bone graft substitute. The interbody fusion rate was 92% (23/25). Mean Oswestry Disability Index (ODI) scores decreased 57.2% at 12 months and 55.6% at 24 months, compared with baseline. CONCLUSIONS: Mineralized collagen bone graft substitute exhibited similar radiographic results compared with autograft in this model. Further trials incorporating bilateral fusion, as well as posterolateral fusion alone without interbody fusion are warranted to confirm the results of this study.

Adult↗
PubMed1987

Immunologic reconstitution after haploidentical bone marrow transplantation for immune deficiency disorders: treatment of bone marrow cells with monoclonal antibody CT-2 and complement.

Patients with congenital T lymphocyte deficiency disorders received transplants with parental bone marrow depleted of mature T cells by the use of an anti-T cell monoclonal antibody (CT-2) and complement. Our results with 16 consecutive patients (20 transplants) showed rapid engraftment of donor cells; cytoreduction (busulfan, cytosine arabinoside [ara-C], cyclophosphamide) was used in six transplants, and marrow ablation was used in six (ara-C, cyclophosphamide, 1,365-cGy total body irradiation). No patient received prophylactic anti-graft-v-host disease (GVHD) therapy posttransplant, and only one patient developed significant GVHD, which involved the skin, liver, and gastrointestinal tract. Seven others showed some manifestations of GVHD, but these were of minimal clinical significance and required only occasional steroid therapy. Overall, eight patients are alive and well; eight did not survive. Polyclonal immunoglobulin synthesis by donor memory B cells was seen shortly after transplantation, with peak donor-derived serum levels seen approximately 2 months after transplantation. After this initial immunoglobulin synthesis waned, another wave of B cell responses developed. This immunoglobulin response appears to be permanent. T cell functions appeared as soon as 3 weeks after transplantation. This experience in a variety of patients with combined immunodeficiency who received transplants with monoclonal antibody T cell-depleted marrow shows gratifying results with a consistent T and B cell benefit.

Adult↗
PubMedDate not supplied

Bone marrow from CD18-/- (MAC-1-/-) homozygous deletion recombinant negative mice demonstrates increased longevity in long-term bone marrow culture and decreased contribution to irradiation pulmonary damage.

BACKGROUND: Bone marrow macrophage surface expression of CD18 (MAC-1, LFA1) is involved in cellular binding to V-CAM-1 and V-CAM-2 adhesion molecules expressed on endothelial cells. We sought to determine if this interaction affected the growth of marrow in long-term bone marrow cultures (LTBMCs) and macrophage migration to the irradiated lung in pulmonary fibrosis/organizing alveolitis. MATERIALS AND METHODS: Continuous bone marrow cultures from CD18-/- and CD18+/+ littermates were established. Bone marrow migration to the irradiated lung was quantitated in CD18+/+ or CD18-/- marrow chimeric mice. Anti-macrophage antibodies were administered to block monocyte/macrophage migration after lung irradiation. RESULTS: CD18-/- LTBMCs demonstrated significantly increased longevity (over 20 weeks) of production of multilineage hematopoietic progenitor cells, total non-adherent cells and macrophage progenitors compared to those derived from CD18+/+ littermates (10 weeks). C57BL/6J female mice chimeric for male CD18-/- bone marrow showed improved (50%) survival at 120 days after pulmonary radiation compared to female mice chimeric for male CD18+/+ bone marrow (0.0%). Intraperitoneal injections (daily for 15 days) of an anti-macrophage antibody on days 80-98 after 20 Gy total lung irradiation resulted in reduction of macrophage migration to the lungs and increased survival. CONCLUSION: The data demonstrate a complex role of CD18 (MAC-1) in macrophage progenitor and macrophage cellular interaction involving stromal cells of the bone marrow and lung.

Animals↗
PubMed1994

Bone marrow transplantation in Australia during 1992. Australian Bone Marrow Transplant Recipient Data Registry.

Australia has a population of 17.5 million people distributed in six states and two territories. The first allogeneic transplants were performed in the early 1970s. There are now 19 hospitals registered with the Australian Bone Marrow Transplant Recipient Data Registry. In 1992 a total of 478 transplant procedures were carried out, of which 228 were allografts and 250 were autografts. The principal indications for allografting were acute leukaemia and chronic myeloid leukaemia; the principal indications for autografting were non-Hodgkin's lymphoma, acute myeloid leukaemia and myeloma. In general the patterns of indications and donor use do not differ from those seen in most European countries and North America.

Acute Disease↗
PubMed1984

Migration of polymorphonuclear neutrophils and macrophages from bone marrow to the peritoneal cavity after (3H)-thymidine labelling of rat tibial bone marrow in vivo.

The kinetics of migration of bone marrow cells to the peritoneal cavity have been studied using in vivo labelling of the marrow of the rat tibia with (methyl-3H)-thymidine (TdR). The incorporation of 3H into DNA is directly related to the amount infused over a thirty-minute period, though only 2-3% of the infused dose is incorporated into DNA in the bone. Autoradiography has shown widespread labelling of bone marrow cells throughout the tibia. Band cells and polymorphonuclear neutrophils (PMN) show an increase in labelling during the 2-3 days after infusion, confirming the maturation of granulocytes prior to their release to the circulation. The disappearance of 3H-labelled DNA from the bone occurs rapidly during the 3 days after infusion of TdR with a half-life (t1/2) of 1.4-1.7 days. There is a concomitant increase in the specific activity of DNA in peritoneal cells elicited by agar, particularly in the macrophage (M phi). Labelling of PMN in the peritoneal exudate occurs only when agar is injected from 2-4 days after infusion of TdR. The time for maturation of PMN in the rat bone marrow (BM) (2-3 days) has been confirmed, and the method of labelling permits both measurement of the migration of cells from BM to peritoneal cavity and an estimate of the rates of migration.

Agar↗
PubMed2005

Expression of interferon-gamma and tumor necrosis factor-alpha in bone marrow T cells and their levels in bone marrow plasma in patients with aplastic anemia.

Immune-mediated stem cell damage has been postulated to be responsible for disease initiation and progression in aplastic anemia (AA). It is hypothesized that T lymphocytes play a major role in destroying the bone marrow (BM) stem cells of AA patients by infiltrating the BM and secreting excessive levels of anti-hematopoietic cytokines, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). We undertook this study to assess the pathogenic significance of anti-hematopoietic cytokines such as IFN-gamma and TNF-alpha in BM T cells and plasma of AA patients. Significantly elevated levels of IFN-gamma and TNF-alpha were found in the BM plasma of AA patients compared to controls (p=0.05 and 0.006, respectively). Intracellular IFN-gamma and not TNF-alpha in BM CD3+ T cells of AA patients was significantly higher compared to controls (p=0.04 and p=0.2, respectively). A follow-up analysis of expression of these cytokines in BM T cells and their levels in BM plasma in five AA patients before and 180 days (6 months) after antithymocyte globulin (ATG) and cyclosporin A (CsA) therapy showed a decline 180 days after therapy compared to pre-therapy. We thus conclude that increased production of both IFN-gamma and TNF-alpha in the BM may contribute to disease pathogenesis in AA and ATG therapy may induce hematological remission by suppressing the elevated levels of IFN-gamma and TNF-alpha in AA BM.

Adolescent↗
PubMed2005

Involvement of subchondral bone marrow in rheumatoid arthritis: lymphoid neogenesis and in situ relationship to subchondral bone marrow osteoclast recruitment.

OBJECTIVE: To evaluate the presence and immunohistochemical characteristics of subchondral bone marrow inflammatory infiltrate in rheumatoid arthritis (RA) and to determine the in situ relationship between marrow inflammation and osteoclast recruitment. METHODS: Bone samples and paired synovia from 8 RA patients undergoing joint surgery were analyzed by immunohistochemistry and in situ hybridization for specific lymphoid neogenetic features, such as T and B cell composition, follicular dendritic cell (FDC) networks, peripheral lymph node addressin (PNAd)-positive high endothelial venules, and lymphoid chemokine expression. Osteoclasts were identified as multinucleated tartrate-resistant acid phosphatase (TRAP)-positive and cathepsin K-positive cells adherent to the bone surface. RESULTS: An inflammatory infiltrate with perivascular aggregates of variable size was detected in 7 (87.5%) of 8 synovial samples and in paired bone samples. Lymphoid neogenetic features typical of rheumatoid synovium were also recognized in the bone marrow. PNAd+ blood vessels were found in 4 of 8 patients, CD21+ FDC networks in 2 patients, CXCL13+ cells in 5 patients, and CCL21+ cells in 6 patients. TRAP-positive and cathepsin K-positive osteoclasts were identified on both the synovial and marrow sides of the bone surface. Bone marrow samples showing a higher degree of inflammation were characterized by a significantly increased number of osteoclasts adherent to the subchondral bone. CONCLUSION: Our data demonstrate that lymphoid aggregates with lymphoid neogenetic features are detectable on the subchondral side of the joint in established RA. Moreover, the local inflammation/aggregation process appears to be related to osteoclast differentiation on the marrow side of subchondral bone, supporting a functional role of the bone compartment in local damage.

Adult↗
PubMed2002

Unique patterns of surface receptors, cytokine secretion, and immune functions distinguish T cells in the bone marrow from those in the periphery: impact on allogeneic bone marrow transplantation.

The "conventional" NK1.1(-) T cells from mouse blood and marrow were compared with regard to surface receptors, cytokine secretion, and function. Most blood NK1.1(-) CD4(+) and CD8(+) T cells expressed the naive CD44(int/lo)CD62L(hi)CD45RB(hi) T-cell phenotype typical of those in the peripheral lymphoid tissues. In contrast, most marrow NK1.1(-) CD4(+) and CD8(+) T cells expressed an unusual CD44(hi)CD62L(hi)CD45RB(hi) phenotype. The blood NK1.1(-) CD4(+) T cells had a naive T-helper cytokine profile and a potent capacity to induce lethal graft versus host (GVH) disease in a C57BL/6 donor to a BALB/c host bone marrow transplantation model. In contrast, the marrow NK1.1(-) CD4(+) T cells had a Th0 cytokine profile and failed to induce lethal GVH disease, even at 20-fold higher numbers than those from the blood. NK1.1(-) CD8(+) T cells from the blood but not the marrow induced lethal GVH disease. Nevertheless, the marrow NK1.1(-) CD8(+) T cells induced potent antitumor activity that was augmented by marrow NK1.1(-) CD4(+) T cells and facilitated hematopoietic progenitor engraftment. The inability of marrow CD4(+) and CD8(+) T cells to induce GVH disease was associated with their inability to expand in the blood and gut of allogeneic recipients. Because neither the purified marrow CD4(+) or CD8(+) T cells induced GVH disease, their unique features are desirable for inclusion in allogeneic bone marrow or hematopoietic progenitor transplants.

Animals↗
PubMed1990

Bone marrow transplantation using unrelated donors for patients with advanced leukemia or bone marrow failure.

Thirty-four patients received bone marrow transplants from unrelated donors. Donors and recipients were phenotypically matched for 6 of 6 HLA-A, B, and DR antigens in 27 cases and at 5 of 6 antigens in 7 cases. Twenty-three patients had leukemia, six had myelodysplasia, and five had aplastic anemia. Twenty-four patients had durable engraftment. Five died of sepsis prior to engraftment. Five patients failed to engraft; 2 of these patients had autologous bone marrow recovery. Seventeen patients developed grade greater than or equal to II acute graft-versus-host disease for an actuarial probability of 67 +/- 20%. The severity of acute graft-versus-host disease and its mortality appeared increased for recipients matched for 5 of 6 HLA-A, B, and DR antigens. Of the 34 patients, 13 (38%) are alive; actuarial survival beyond 6 months is 44 +/- 17%. None of the 25 leukemia and myelodysplasia patients achieving engraftment have relapsed. For leukemia and myelodysplasia recipients of 6 of 6 HLA-matched grafts, actuarial survival at 6 months was 55 +/- 21% compared with 14 +/- 26% for recipients matched for 5 of 6 HLA loci (P = 0.19). Infection and acute graft-versus-host disease were the primary causes of death in the engrafted patients. Survival for aplastic anemia patients was 20%. Late deaths due to pneumonia and bronchiolitis obliterans occurred after one year in 2 patients. Closely matched unrelated donor bone marrow transplants are associated with a higher incidence of graft failure and graft-versus-host disease than typically reported for transplants from HLA-identical siblings, but these preliminary data suggest a lower rate of relapse.

Acute Disease↗
PubMed2005

Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptin-deficient ob/ob mice.

UNLABELLED: Normal mice and leptin-deficient ob/ob mice were treated with leptin to study effects on osteogenesis and adipogenesis in bone marrow. Leptin treatment significantly decreased bone marrow adipocyte size and number in ob/ob mice while increasing bone formation, BMC, and BMD. The results suggest that, in leptin-sensitive animals, the reduction in marrow adipocytes has positive effects on bone formation. INTRODUCTION: Adipocytes, osteoblasts, and osteoclasts have leptin receptors, and leptin can also affect bone metabolism indirectly through its receptors in the hypothalamus. We examined the effects of leptin treatment on bone formation, BMD, and marrow adipocyte population in normal mice and leptin-deficient ob/ob mice. MATERIALS AND METHODS: At the age of 15 weeks, mice were implanted with Alzet osmotic pumps for subcutaneous delivery of treatment solutions (saline, 2.5 microg leptin/day, or 10 microg leptin/day) for 14 days at a delivery rate of 0.25 microl/h. Bone formation was assessed using fluorochrome labels, cell populations were quantified using histomorphometry, and bone densitometry was measured using DXA. We also used a Luminex Beadlyte assay system to quantify cell survival markers in bone marrow samples. RESULTS AND CONCLUSIONS: Results indicate that both doses of leptin decreased the number of marrow adipocytes in ob/ob mice by >20% (p < 0.05) compared with PBS-treated ob/ob mice. The decrease in adipocyte number with leptin treatment is accompanied by an increase in concentration of the apoptosis marker caspase-3 in bone marrow adipocytes and hematopoietic cells. Both leptin doses also significantly (p < 0.05) increased the percentage of fluorochrome-labeled tibial endosteal surface by >30% compared with PBS-treated ob/ob mice. Leptin treatment increased whole body BMC by >30% in the ob/ob mice receiving the highest leptin dose. Leptin treatment provided no increase in bone formation, BMC, or BMD in normal, leptin-replete mice.

Adipocytes↗