title: Demonstration of an osteoblast defect in two cases of human malignant osteopetrosis. Correction of the phenotype after bone marrow transplant.
abstract: Osteopetrosis is an inherited disorder characterized by bone sclerosis due to reduced bone resorption. Here we report that human osteopetrotic osteoblast-like (Ob) cells express a defective phenotype in primary cultures in vitro, and that bone marrow transplant (BMT) corrects osteoblast function. DNA analysis at polymorphic short-tandem repeat loci from donor, recipient, and primary Ob-like cells pre-BMT and 2 yr post-BMT revealed that Ob were still of recipient origin post-BMT. Osteopetrotic Ob-like cells obtained pre-BMT showed normal and abnormal 1,25(OH)2D3-induced alkaline phosphatase (ALPase) and osteocalcin production, respectively, and failed to produce macrophage colony-stimulating factor (M-CSF) in response to IL-1a and TNF-alpha. These parameters were all normalized in primary Ob-like cells prepared 2 yr post-BMT. X-linked clonality analysis at the human androgen receptor (HUMARA) locus revealed that osteoblasts showed a polyclonal and an oligoclonal derivation pre- and post-BMT respectively, indicating that a limited number of progenitor reconstituted this population. Because osteoblasts were still of recipient origin post-BMT, this suggests that functional osteoclasts, due to the replacement of hematopoeitic cells, provided a local microenvironment in vivo triggering the differentiation and/or recruitment of a limited number of functional osteoblasts.
authors.affiliation: Centre de Recherche Guy Bernier et Unité de Greffe de Moëlle Osseuse,Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Lajeunesse
authors.forename: L
authors.initials: L
authors.lastname: Busque
authors.forename: P
authors.initials: P
authors.lastname: Ménard
authors.forename: M G
authors.initials: MG
authors.lastname: Brunette
authors.forename: Y
authors.initials: Y
authors.lastname: Bonny
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis; D016026:Bone Marrow Transplantation; D002117:Calcitriol / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D010006:Osteoblasts / Q000502:physiology*; D015675:Osteocalcin / Q000096:biosynthesis; D010022:Osteopetrosis / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics; D014960:X Chromosome
chemical_list: D011944:Receptors, Androgen; D015675:Osteocalcin; D016173:Macrophage Colony-Stimulating Factor; D000469:Alkaline Phosphatase; D002117:Calcitriol