title: Imbalance of the osteoprotegerin/RANKL ratio in bone marrow microenvironment after allogeneic hemopoietic stem cell transplantation.
abstract: BACKGROUND
  Bone loss is a common complication after allogeneic stem cell transplantation. Osteoprotegerin (OPG) plays a critical role in bone remodeling by neutralizing the effect of receptor activator of nuclear factor-kappaB ligand (RANKL) on differentiation and activation of osteoclasts. We investigated OPG and RANKL in serum and marrow plasma in transplanted patients.
  
  
  METHODS
  In 36 patients and 36 controls, the relationships among bone mineral density, circulating OPG, RANKL, interferon-gamma, and interleukin-6 levels were investigated; in addition, OPG and RANKL were measured in marrow plasma and in conditioned medium of long-term cultures of marrow mesenchymal-derived osteogenic cells.
  
  
  RESULTS
  Lumbar and femoral bone mineral density were lower in patients than in controls (P<0.01). Serum OPG (sOPG) and interferon-gamma were significantly higher in patients than in controls (P<0.05). Patients' interferon-gamma correlated with sOPG levels (r=0.4; P=0.03). Interleukin-6 did not differ between patients and controls. By contrast, OPG levels were lower in patients than in controls in marrow plasma (P<0.001) and in conditioned media after one (P=0.035) and three months (P=0.003) of culture of marrow mesenchymal-derived osteogenic cells. RANKL was similar in patients and controls. The OPG/RANKL ratio "in situ" was significantly lower in patients than in controls (P<0.05). There was no correlation between sOPG and marrow OPG, RANKL levels, densitometric values, and chronic graft-versus-host disease.
  
  
  CONCLUSIONS
  Our findings suggest that after allogeneic stem cell transplantation: 1) sOPG bear no relationship with OPG in the bone marrow; 2) increased sOPG can be the result of its enhanced production in extra bone tissues triggered by inflammatory cytokines; 3) low bone marrow OPG levels may be partly related to the persistent quantitative and qualitative deficit of osteoblastic precursors; and 4) reduced OPG/RANKL ratio in bone microenvironment may increase bone remodeling by promoting bone resorption.
authors.affiliation: Department of Biochemistry and Medical Biotechnology, Hematology Branch, Federico II University of Naples, Naples, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ricci
authors.forename: Libuse
authors.initials: L
authors.lastname: Tauchmanova
authors.forename: Antonio Maria
authors.initials: AM
authors.lastname: Risitano
authors.forename: Carlo
authors.initials: C
authors.lastname: Carella
authors.forename: Gherardo
authors.initials: G
authors.lastname: Mazziotti
authors.forename: Gaetano
authors.initials: G
authors.lastname: Lombardi
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.forename: Bruno
authors.initials: B
authors.lastname: Rotoli
authors.forename: Carmine
authors.initials: C
authors.lastname: Selleri
mesh_terms: D015502:Absorptiometry, Photon; D000293:Adolescent; D000328:Adult; D015519:Bone Density; D001853:Bone Marrow / Q000737:chemistry*; D001862:Bone Resorption / Q000209:etiology*; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D053244:Osteoprotegerin / Q000032:analysis* / Q000097:blood / Q000378:metabolism; D053245:RANK Ligand / Q000032:analysis* / Q000097:blood / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand