Autosomal recessive osteopetrosis (ARO) is a severe bone disease characterized by increased bone density due to impairment in osteoclast resorptive function or differentiation. Hematopoietic stem cell transplantation is the only available treatment; however, this therapy is not effective in RANKL-dependent ARO, since in bone this gene is mainly expressed by cells of mesenchymal origin. Of note, whether lack of RANKL production might cause a defect also in the bone marrow (BM) stromal compartment, possibly contributing to the pathology, is unknown. To verify this possibility, we generated and characterized BM mesenchymal stromal cell (BM-MSC) lines from wild type and Rankl−/− mice, and found that Rankl−/− BM-MSCs displayed reduced clonogenicity and osteogenic capacity. The differentiation defect was significantly improved by lentiviral transduction of Rankl−/− BM-MSCs with a vector stably expressing human soluble RANKL (hsRANKL). Expression of Rankl receptor, Rank, on the cytoplasmic membrane of BM-MSCs pointed to the existence of an autocrine loop possibly activated by the secreted cytokine. Based on the close resemblance of RANKL-defective osteopetrosis in humans and mice, we expect that our results are also relevant for RANKL-dependent ARO patients. Data obtained in vitro after transduction with a lentiviral vector expressing hsRANKL would suggest that restoration of RANKL production might not only rescue the defective osteoclastogenesis of this ARO form, but also improve a less obvious defect in the osteoblast lineage, thus possibly achieving higher benefit for the patients, when the approach is translated to clinics.
Murine Rankl−/− Mesenchymal Stromal Cells Display an Osteogenic Differentiation Defect Improved by a RANKL-Expressing Lentiviral Vector / F. Schena, C. Menale, E. Caci, L. Diomede, E. Palagano, C. Recordati, M. Sandri, A. Tampieri, I. Bortolomai, V. Capo, C. Pastorino, A. Bertoni, M. Gattorno, A. Martini, A. Villa, E. Traggiai, C. Sobacchi. - In: STEM CELLS. - ISSN 1066-5099. - 35:5(2017), pp. 1365-1377.
|Titolo:||Murine Rankl−/− Mesenchymal Stromal Cells Display an Osteogenic Differentiation Defect Improved by a RANKL-Expressing Lentiviral Vector|
|Parole Chiave:||Bone; Differentiation; Lentiviral transduction; Mesenchymal stromal cell; Osteopetrosis; Rankl; Animals; Biomarkers; Clone Cells; Genetic Vectors; Immunophenotyping; Lentivirus; Mesenchymal Stem Cells; Mice, Inbred C57BL; RANK Ligand; Signal Transduction; Transduction, Genetic; Cell Differentiation; Osteogenesis|
|Settore Scientifico Disciplinare:||Settore VET/03 - Patologia Generale e Anatomia Patologica Veterinaria|
|Data di pubblicazione:||2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/stem.2574|
|Appare nelle tipologie:||01 - Articolo su periodico|