- Prostate Cancer and Bone Metastases: The Underlying Mechanisms. [Review]
- IJInt J Mol Sci 2019 May 27; 20(10)
- Patients with advanced prostate cancer often develop bone metastases, leading to bone pain, skeletal fracture, and increased mortality. Bone provides a hospitable microenvironment to tumor cells. The…
Patients with advanced prostate cancer often develop bone metastases, leading to bone pain, skeletal fracture, and increased mortality. Bone provides a hospitable microenvironment to tumor cells. The disease manifestation is driven by the interaction between invading tumor cells, bone-forming osteoblasts, and bone-resorbing osteoclasts. The increased level of osteoclast-activating factor (parathyroid hormone-related peptide, PTHrP) is believed to induce bone resorption by upregulating receptor activator of nuclear factor-kappa B ligand (RANKL) and the release of various growth factors into the bone microenvironment to enhance cancer cell growth. However, the underlying molecular mechanisms remain poorly understood. This review outlines the possible molecular mechanisms involved in governing bone metastases driven by prostate cancer, which further provide the basis in searching for new molecular targets for the development of potential therapy.
- Puerarin Prevents LPS-Induced Osteoclast Formation and Bone Loss via Inhibition of Akt Activation. [Journal Article]
- BPBiol Pharm Bull 2016; 39(12):2028-2035
- Osteolysis induced by chronic Gram-negative bacterial infection underlies many bone diseases such as osteomyelitis, septic arthritis, and periodontitis. Drugs that inhibit lipopolysaccharide (LPS)-in…
Osteolysis induced by chronic Gram-negative bacterial infection underlies many bone diseases such as osteomyelitis, septic arthritis, and periodontitis. Drugs that inhibit lipopolysaccharide (LPS)-induced osteolysis are critically needed for the prevention of bone destruction in infective bone diseases. In this study, we assessed the effect of puerarin, a natural isoflavone isolated from Pueraria lobata OHWI root, on LPS-induced osteoclastogenesis and bone loss. Our in vitro study showed that puerarin significantly inhibited LPS-induced osteoclast differentiation from osteoclast precursor RAW264.7 cells. The inhibition occurred through suppressing the production of osteoclast activating factor tumor necrosis factor (TNF)-α, interleukin (IL)-1β and prostaglandin E2 (PGE2), which led to down-regulating mRNA expression of osteoclastogenic genes including tartrate-resistant acid phosphatase (TRAP), cathepsin K and matrix metalloprotein 9 (MMP-9). Furthermore, LPS triggered activation of Akt in osteoclast precursor RAW264.7 cells, which was inhibited by puerarin treatment. In vivo, puerarin attenuated LPS-induced bone loss in a murine calvarial osteolysis model. Collectively, puerarin prevents LPS-induced osteoclast formation, function and bone loss, where the inhibition of Akt activation plays an important role. These findings provide evidences that puerarin might be beneficial as a promising candidate drug for the prevention and treatment of bacteria-induced bone destruction disease, and give new insights for understanding its possible mechanism.
- Effect of The Receptor Activator of Nuclear Factor кB and RANK Ligand on In Vitro Differentiation of Cord Blood CD133(+) Hematopoietic Stem Cells to Osteoclasts. [Journal Article]
- CJCell J 2016; 18(3):322-31
- CONCLUSIONS: Presence of RANKL and M-CSF in bone marrow could induce HSCs differentiation into osteoclast.
- A successful treatment of hypercalcemia with zoledronic acid in a 15-year-old boy with acute lymphoblastic leukemia. [Journal Article]
- APAnn Pediatr Endocrinol Metab 2016; 21(2):99-104
- Severe hypercalcemia in children is a rare medical emergency. We present a case of a 15-year-old boy with hypercalcemia (total calcium level, 14.2 mg/dL) with a normal complete blood count, no circul…
Severe hypercalcemia in children is a rare medical emergency. We present a case of a 15-year-old boy with hypercalcemia (total calcium level, 14.2 mg/dL) with a normal complete blood count, no circulating blasts in the peripheral blood film, and no other signs of acute lymphoblastic leukemia (ALL), including no signs of lymphadenopathy or hepatosplenomegaly. The hypercalcemia was successfully treated with zoledronic acid. As hypercalcemia can be the only presenting symptom of ALL in children, the diagnosis is often delayed. In children presenting with hypercalcemia, malignancies must be considered in the differential diagnosis.
- Increased serum levels of MIP-1alpha correlate with bone disease and angiogenic cytokines in patients with multiple myeloma. [Journal Article]
- MOMed Oncol 2014; 31(1):778
- Many cytokines possess variable roles in the pathogenesis of multiple myeloma. Macrophage inflammatory protein-1alpha (MIP-1alpha) is an osteoclast-activating factor with a major role in myeloma bone…
Many cytokines possess variable roles in the pathogenesis of multiple myeloma. Macrophage inflammatory protein-1alpha (MIP-1alpha) is an osteoclast-activating factor with a major role in myeloma bone disease. The aim of the study was to examine its participation in the angiogenic process of the disease. We measured, by enzyme-linked immunosorbent assays, its serum levels in 56 newly diagnosed myeloma patients, in several skeletal grades and stages of the disease and in 25 healthy controls. Concurrently, we measured serum levels of the angiogenic cytokines basic-fibroblast growth factor, hepatocyte growth factor and interleukin-18. All the above cytokines were higher in myeloma patients (p < 0.001 for all cases) and were increasing in parallel with disease stage (p < 0.001 for all cases) and skeletal grade (p < 0.04 for MIP-1alpha and p < 0.001 for the other cases). Moreover, positive correlations between MIP-1alpha and all the angiogenic cytokines were noted (p < 0.001 for all cases). MIP-1alpha seems to be a predominant factor responsible for the enhancement of bone resorption and increased angiogenesis. The positive correlation between MIP-1alpha and the angiogenic chemoattractants supports the involvement of these factors in the biology of myeloma cell growth. Moreover, they could be used as possible therapeutic targets as well as markers of disease activity.
- Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells. [Journal Article]
- HHaematologica 2014; 99(1):163-71
- Multiple myeloma is an incurable hematologic cancer characterized by the clonal proliferation of malignant plasma cells within the bone marrow. Numerous studies suggest that the myeloma plasma cells …
Multiple myeloma is an incurable hematologic cancer characterized by the clonal proliferation of malignant plasma cells within the bone marrow. Numerous studies suggest that the myeloma plasma cells occupy and alter the stromal tissue of the bone marrow as a means of enhancing their survival and growth. However, the nature and magnitude of the changes to the stromal cell tissue remain to be determined. In this study, we used mesenchymal stromal cell and osteoblast-related cell surface marker expression (STRO-1 and alkaline phosphatase, respectively) and flow cytometry to enumerate mesenchymal stromal cell and osteoblast numbers in bone marrow recovered from myeloma patients at the time of diagnosis. Using this approach, we identified an increase in the number of STRO-1 positive colony forming mesenchymal stromal cells and a concomitant decrease in alkaline phophatase osteoblasts. Notably, this increase in mesenchymal stromal cell numbers correlated closely with plasma cell burden at the time of diagnosis. In addition, in comparison with the osteoblast population, the STRO-1+ mesenchymal stromal cell population was found to express higher levels of plasma cell- and osteoclast-activating factors, including RANKL and IL-6, providing a mechanism by which an increase in mesenchymal stromal cells may promote and aid the progression of myeloma. Importantly, these findings were faithfully replicated in the C57BL/KaLwRij murine model of myeloma, suggesting that this model may present a unique and clinically relevant system in which to identify and therapeutically modulate the bone microenvironment and, in turn, alter the progression of myeloma disease.
- Osteoblast and osteoclast crosstalks: from OAF to Ephrin. [Review]
- IAInflamm Allergy Drug Targets 2012; 11(3):196-200
- The maintenance of bone homeostasis is tightly controlled, and largely dependent upon cellular communication between osteoclasts and osteoblasts, and the coupling of bone resorption to bone formation…
The maintenance of bone homeostasis is tightly controlled, and largely dependent upon cellular communication between osteoclasts and osteoblasts, and the coupling of bone resorption to bone formation. This tight coupling is essential for the correct function and maintenance of the skeletal system, repairing microscopic skeletal damage and replacing aged bone. Cells in osteoclast and osteoblast lineages communicate with each other through diffusible paracrine factors, cell-cell contact, and cell-bone matrix interaction. Osteoclast-osteoblast communication occurs in a basic multicellular unit (BMU) at the initiation, transition and termination phases of bone remodeling. At the initiation phase, hematopoietic precursors are recruited to the BMU. These precursors differentiate into osteoclasts following interactions with osteoblasts, which express and/or secrete ligands as RANK-L and OPG. Subsequently, the transition from bone resorption to formation is mediated by osteoclast-derived 'coupling factors', which direct the differentiation and activation of osteoblasts in resorbed lacunae to refill it with new bone. Signals derived from molecules released from the resorbed bone matrix, as TGF-beta and bidirectional signaling generated by interaction between ephrinB2 on osteoclasts and EphB4 on osteoblast precursors facilitates the transition. At the termination phase, bone remodeling is completed by osteoblastic bone formation and mineralization of bone matrix. The research steps that brought to the present knowledge are summarized in this review.
- Bone microstructural changes revealed by high-resolution peripheral quantitative computed tomography imaging and elevated DKK1 and MIP-1α levels in patients with MGUS. [Journal Article]
- BloodBlood 2011 Dec 15; 118(25):6529-34
- Recent population-based studies demonstrate an increased fracture risk with monoclonal gammopathy of undetermined significance (MGUS). The etiology of this increased risk remains unclear, however, be…
Recent population-based studies demonstrate an increased fracture risk with monoclonal gammopathy of undetermined significance (MGUS). The etiology of this increased risk remains unclear, however, because areal bone mineral density (aBMD) measurements by dual-energy x-ray absorptiometry cannot assess bone microstructural properties critical to determining bone quality and strength. To better define the skeletal effects of MGUS, we performed aBMD and high-resolution peripheral quantitative computed tomography volumetric bone mineral density (vBMD) measurements in 50 MGUS patients (20 females, 30 males; mean ± SEM age, 70.5 ± 1.4 years) and 100 matched control subjects. Relative to controls, MGUS patients had decreased aBMD at the femoral neck (P = .05) and total femur (P < .05) but no differences at other sites. In contrast, high-resolution peripheral quantitative computed tomography showed markedly diminished cortical thickness (P < .05) and increased endocortical area (P < .01). Average vBMD (P < .01), cortical vBMD (P < .001), and trabecular thickness (P < .01) were all significantly decreased in MGUS patients, suggestive of impaired bone formation. Serum levels of the Wnt pathway inhibitor Dickkopf-related protein 1 (P < .001) and osteoclast-activating factor MIP-1α (P < .05) also were significantly elevated in MGUS patients. Our data provide the first evidence of altered bone microstructure in MGUS and suggest that cytokines elevated in osteolytic myeloma also may be associated with bone loss in MGUS.
- Over-expression of CCL3 MIP-1alpha in a blastoid mantle cell lymphoma with hypercalcemia. [Case Reports]
- EJEur J Haematol 2010; 84(5):448-52
- We analyzed a case with the blastoid variant of mantle cell lymphoma (MCL-BV), a rare subtype of B-cell lymphoma, presenting with marked hypercalcemia at diagnosis. Enzyme-linked immunosorbent assay …
We analyzed a case with the blastoid variant of mantle cell lymphoma (MCL-BV), a rare subtype of B-cell lymphoma, presenting with marked hypercalcemia at diagnosis. Enzyme-linked immunosorbent assay (ELISA) showed elevated serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), and type I collagen telopeptide, but not parathyroid hormone, calcitriol or parathyroid hormone-related peptide at diagnosis, suggesting local osteoclastic hypercalcemia in this case. By reverse transcription polymerase chain reaction (RT-PCR) analysis, we found predominant expression of mRNA for MIP-1alpha in addition to those for receptor-activator of nuclear-factor kappa B ligand (RANKL), TNF-alpha, and IL-6 in lymphoma cells obtained from the patient. Furthermore, recombinant MIP-1alpha significantly stimulated (3)H-thymidine uptake by isolated MCL cells in vitro. Treatment with intravenous fluids, bisphosphonate, and methylprednisolone followed by combination chemotherapy promptly corrects the hypercalcemia and successfully induced complete remission, which was accompanied by a decrease of these cytokines in the serum, including MIP-1alpha. In the present case, MIP-1alpha, an osteoclast-activating factor produced by mantle lymphoma cells, may contribute to the development of hypercalcemia. It likely acts through RANKL expression in tumor cells and/or stroma cells, as indicated in multiple myeloma (MM) and adult T-cell leukemia/lymphoma (ATLL). Furthermore, MIP-1alpha is also involved in the development of an aggressive phenotype on MCL by stimulating proliferation of these lymphoma cells. In summary, the present study demonstrated that MIP-1alpha is an important factor in the development of both hypercalcemia and an aggressive phenotype in some types of B-cell lymphoma.
New Search Next
- [Bone remodeling: new therapeutic approaches]. [Review]
- RMRev Med Suisse 2009 Jun 10; 5(207):1325-8
- High bone remodeling leads to bone loss and microarchitectural deteriorations characteristic of osteoporosis. Bisphosphonates and selective estrogen receptor modulators decrease bone remodeling by pr…
High bone remodeling leads to bone loss and microarchitectural deteriorations characteristic of osteoporosis. Bisphosphonates and selective estrogen receptor modulators decrease bone remodeling by preventing osteoclast-mediated bone resorption, whereas parathyroid hormone/teriparatide increase bone remodeling in favor of new bone formation. Better understanding of the molecular processes of bone remodeling has led to the development of agents to inhibit bone resorption, such as the human monoclonal antibody Denosumab targeting osteoclast-activating factor RANK Ligand, and odanacatib targeting the collagen-degrading enzyme cathepsin K. Agents capable to stimulate bone formation independently of bone resorption, such as antagonists of the osteoblast-inhibitory factor sclerostin, may provide new therapeutic approaches to osteoporosis.