osteoprotegerin and Hematologic-Diseases

This review will focus on the emerging role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptors in the pathophysiology of hematopoiesis and on the potential therapeutic applications of either recombinant TRAIL or anti-TRAIL-R1/-R2 agonistic antibodies for the treatment of hematological malignancies.. While CD34 stem/progenitor cells do not express TRAIL-receptors and are protected from TRAIL-induced apoptosis, accumulating evidence points to a role for elevated expression/release of TRAIL at the bone marrow level in the pathophysiology of aplastic anemia, Fanconi anemia, and myelodysplastic syndromes. In-vitro data show promising synergistic effects of recombinant TRAIL in association with proteasome or histone deacetylase inhibitors, natural compounds or small molecules in the therapy of myeloid and lymphoid malignancies. Moreover, although both recombinant TRAIL and anti-TRAIL-R1/-R2 antibodies are well tolerated in vivo, anti-TRAIL-R1/-R2 agonistic antibodies show the potential advantage of avoiding the neutralizing activity of the soluble receptor osteoprotegerin.. While a chronic pathological elevation of TRAIL at the bone marrow level might contribute to the impairment of normal hematopoiesis, the use of recombinant TRAIL and anti-TRAIL-R1/-R2 agonistic antibodies appears particularly promising for the treatment of hematological malignancies in particular, of multiple myeloma, especially if used in association with innovative therapeutic compounds.

Topics: Animals; Apoptosis; Bone Marrow; Combined Modality Therapy; Hematologic Diseases; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Stem Cells; Humans; Mice; Mice, Knockout; Osteoprotegerin; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; Recombinant Proteins; TNF-Related Apoptosis-Inducing Ligand

We report on a case of osteoclast-poor osteopetrosis who received a hematopoietic stem cell graft and, despite hematological engraftment, showed little signs of response in the skeletal defect. Clinical and laboratory studies supported the concept that the bone microenvironment remained abnormal, thus reducing the clinical response to transplantation.. Osteopetrosis is a rare genetic disorder characterized by severely reduced bone resorption resulting from a defect in either osteoclast development (osteoclast-poor osteopetrosis) or activation (osteoclast-rich osteopetrosis). Patients with osteoclast-rich osteopetrosis can be rescued by allogenic hematopoietic stem cell transplantation; however, little information exists concerning the success of transplantation as a treatment for osteoclast-poor osteopetrosis. We report on a child with osteoclast-poor osteopetrosis whose diagnosis was delayed, consequently receiving a cord blood transplant from an unrelated donor at the age of 8 years. Engraftment was deemed successful by peripheral blood genotyping, although >3 years after transplantation there was little rescue of the skeletal defect and anemia, and extramedullary hematopoiesis persisted.. Peripheral blood mononuclear cells from the osteopetrosis patient, before and after transplantation, were used to generate osteoclasts in vitro in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL.. Before transplantation few, small mononuclear osteoclasts formed (F-actin ring-positive cells, co-localizing with vitronectin receptor [alphavbeta3 integrin] and TRACP) associated with occasional, small resorption lacunae. Low levels of collagen C-terminal telopeptide (CTx) fragments were released from these cultures as assessed by ELISA (CrossLaps; patient, 12.85 nM; control, 448.6 nM). In contrast, osteoclasts formed in cultures after transplantation formed to a similar degree to control cultures from healthy individuals: large numbers of osteoclasts containing numerous nuclei were present, and approximately 50% of the surface of bone slices was resorbed, associated with intermediate levels of collagen fragment release (116.48 nM). The culture data reflect the histopathology and radiological findings and also support previous studies showing that neither M-CSF nor RANKL rescues osteoclast-poor osteopetrosis.. This is the first case reported in which a successful hematopoietic engraftment failed to correct an osteopetrotic skeletal defect, and this finding may be credited to the age at which the child was transplanted.

Topics: Acid Phosphatase; Biopsy; Carrier Proteins; Cartilage; CD11c Antigen; CD18 Antigens; Cell Differentiation; Child; Collagen; Collagen Type I; Cord Blood Stem Cell Transplantation; DNA Mutational Analysis; Female; Femur; Glycoproteins; Hematologic Diseases; Humans; Humerus; Integrin alphaVbeta3; Isoenzymes; Leukocytes, Mononuclear; Macrophage Colony-Stimulating Factor; Membrane Glycoproteins; Osteoclasts; Osteopetrosis; Osteoprotegerin; Peptides; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tartrate-Resistant Acid Phosphatase; Transplantation, Homologous; Treatment Outcome