title: Mechanisms of osteoclast dysfunction in human osteopetrosis: abnormal osteoclastogenesis and lack of osteoclast-specific adhesion structures.
abstract: Osteoclasts from a patient affected by osteopetrosis were examined in vivo and in vitro. Iliac crest biopsy revealed an osteosclerotic pattern, with prominent numbers of osteoclasts noted for hypernuclearity and incomplete adherence to the bone surface. A population comprising tartrate-resistant acid phosphatase (TRAP)-positive, multinucleated and mononuclear cells, and alkaline phosphatase-positive stromal fibroblasts was obtained in vitro from bone marrow. Mononuclear TRAP-positive precursors spontaneously fused in culture to form giant osteoclast-like cells. These cells expressed the osteoclast marker MMP-9 and calcitonin receptor, and lacked the macrophage marker, Fc receptor. Expression and distribution of c-src, c-fms, and CD68, and response to steroid hormones relevant to osteoclast differentiation and function were apparently normal, whereas cell retraction in response to calcitonin was impaired. TRAP-positive multinucleated cells did not form osteoclast-specific adhesion structures (clear zone, podosomes, or actin rings). Bone resorption rate was severely reduced in vitro. Focal adhesions and stress fibers were observed en lieu of podosomes and actin rings. Adhesion structures contained low levels of immunoreactive vitronectin receptor, most of this integrin being retained in cytoplasmic vesicles. These data provide the first characterization of abnormal differentiation and function of human osteopetrotic osteoclast-like cells.
authors.affiliation: Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Teti
authors.forename: S
authors.initials: S
authors.lastname: Migliaccio
authors.forename: A
authors.initials: A
authors.lastname: Taranta
authors.forename: S
authors.initials: S
authors.lastname: Bernardini
authors.forename: G
authors.initials: G
authors.lastname: De Rossi
authors.forename: M
authors.initials: M
authors.lastname: Luciani
authors.forename: M
authors.initials: M
authors.lastname: Iacobini
authors.forename: L
authors.initials: L
authors.lastname: De Felice
authors.forename: R
authors.initials: R
authors.lastname: Boldrini
authors.forename: C
authors.initials: C
authors.lastname: Bosman
authors.forename: A
authors.initials: A
authors.lastname: Corsi
authors.forename: P
authors.initials: P
authors.lastname: Bianco
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002116:Calcitonin / Q000494:pharmacology; D002448:Cell Adhesion; D002648:Child; D005260:Female; D005455:Fluorescent Antibody Technique; D016391:Genes, src; D006651:Histocytochemistry; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008854:Microscopy, Electron; D010010:Osteoclasts / Q000473:pathology* / Q000648:ultrastructure; D010022:Osteopetrosis / Q000473:pathology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D018003:Receptors, Calcitonin / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D000097382:CD68 Molecule
chemical_list: D000135:Acid Phosphatase; D000469:Alkaline Phosphatase; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002116:Calcitonin; D007527:Isoenzymes; D016186:Receptor, Macrophage Colony-Stimulating Factor; D018003:Receptors, Calcitonin; D019030:Receptors, Vitronectin; D000071681:Tartrate-Resistant Acid Phosphatase; C067980:CD68 antigen, human; D000097382:CD68 Molecule