title: Osteoclasts from mice deficient in tartrate-resistant acid phosphatase have altered ruffled borders and disturbed intracellular vesicular transport.
abstract: Tartrate-resistant acid phosphatase (TRAP) is an enzyme highly expressed in osteoclasts (OC) and chondroclasts. As an approach to pinpoint the function of TRAP in bone-resorbing osteoclasts, the morphological phenotypic alterations of bone and osteoclasts in mice with targeted disruption of the TRAP gene were assessed by quantitative histomorphometry and immunocytochemistry at the light microscopic and ultrastructural levels. TRAP-deficient mice display alterations in the epiphyseal growth plates as evidenced by increased height with disorganized columns of chondrocytes, in particular affecting the zone of hypertrophic chondrocytes, consistent with a disturbance of chondrocyte maturation and chondroclastic resorption at the epiphyseal/metaphyseal junction. TRAP -/- mice express an early onset osteopetrotic bone phenotype, apparent already at 4 weeks of age. The differentiation of OCs was apparently normal; however, the osteoclasts in TRAP-deficient mice were less active in terms of degradation or release of the resorption marker C-terminal type I collagen cross-linked peptide, indicative of an intrinsic defect. Ultrastructural morphometry disclosed that OCs from TRAP-deficient young mice exhibited an increased relative area of ruffled borders. Moreover, mutant OC accumulated cytoplasmic vesicles 200-500 nm in size in both ruffled border and basolateral parts of the cytoplasm, reflecting disturbed intracellular transport. The accumulated vesicles were not likely derived from the secretory pathway, since cathepsin K was detected at normal levels in the ruffled border area and matrix in TRAP -/- mice. In summary, the resorptive defect in TRAP-deficient OCs is reflected by a disturbance at the level of ruffled borders and intracellular transport vesicles. Consequently, accumulation of vesicles in the cytoplasm of mutant OCs indicates a novel function for TRAP in modulating intracellular vesicular transport in osteoclasts.
authors.affiliation: Division of Pathology, Karolinska Institutet, Huddinge University Hospital, SE-141 86, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Hollberg
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.forename: Alison
authors.initials: A
authors.lastname: Hayman
authors.forename: Timothy
authors.initials: T
authors.lastname: Cox
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
mesh_terms: D000135:Acid Phosphatase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D022081:Cell Surface Extensions / Q000378:metabolism*; D005269:Femur / Q000033:anatomy & histology / Q000502:physiology; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism* / Q000648:ultrastructure; D021381:Protein Transport / Q000502:physiology*; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D007527:Isoenzymes; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse