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1.
J Bone Miner Res ; 27(2): 413-28, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22028304

ABSTRACT

Progeny of mice treated with the mutagen N-ethyl-N-nitrosourea (ENU) revealed a mouse, designated Longpockets (Lpk), with short humeri, abnormal vertebrae, and disorganized growth plates, features consistent with spondyloepiphyseal dysplasia congenita (SEDC). The Lpk phenotype was inherited as an autosomal dominant trait. Lpk/+ mice were viable and fertile and Lpk/Lpk mice died perinatally. Lpk was mapped to chromosome 15 and mutational analysis of likely candidates from the interval revealed a Col2a1 missense Ser1386Pro mutation. Transient transfection of wild-type and Ser1386Pro mutant Col2a1 c-Myc constructs in COS-7 cells and CH8 chondrocytes demonstrated abnormal processing and endoplasmic reticulum retention of the mutant protein. Histology revealed growth plate disorganization in 14-day-old Lpk/+ mice and embryonic cartilage from Lpk/+ and Lpk/Lpk mice had reduced safranin-O and type-II collagen staining in the extracellular matrix. The wild-type and Lpk/+ embryos had vertical columns of proliferating chondrocytes, whereas those in Lpk/Lpk mice were perpendicular to the direction of bone growth. Electron microscopy of cartilage from 18.5 dpc wild-type, Lpk/+, and Lpk/Lpk embryos revealed fewer and less elaborate collagen fibrils in the mutants, with enlarged vacuoles in the endoplasmic reticulum that contained amorphous inclusions. Micro-computed tomography (CT) scans of 12-week-old Lpk/+ mice revealed them to have decreased bone mineral density, and total bone volume, with erosions and osteophytes at the joints. Thus, an ENU mouse model with a Ser1386Pro mutation of the Col2a1 C-propeptide domain that results in abnormal collagen processing and phenotypic features consistent with SEDC and secondary osteoarthritis has been established.


Subject(s)
Collagen Type II/genetics , Mutation, Missense/genetics , Osteoarthritis/complications , Osteoarthritis/genetics , Osteochondrodysplasias/congenital , Amino Acid Sequence , Animals , Base Sequence , Chondrocytes/metabolism , Chondrocytes/pathology , Chondrocytes/ultrastructure , Chromosomes, Mammalian/genetics , Collagen Type II/chemistry , Disease Models, Animal , Embryo, Mammalian/abnormalities , Embryo, Mammalian/pathology , Genetic Loci/genetics , Growth Plate/abnormalities , Growth Plate/pathology , Male , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Mutant Proteins/metabolism , Organ Size , Osteochondrodysplasias/complications , Osteochondrodysplasias/genetics , Osteogenesis , Phenotype , Physical Chromosome Mapping , Protein Processing, Post-Translational
2.
J Immunol ; 186(5): 2910-7, 2011 Mar 01.
Article in English | MEDLINE | ID: mdl-21278350

ABSTRACT

Invariant NKT (iNKT) cells modulate innate and adaptive immune responses through activation of myeloid dendritic cells and macrophages and via enhanced clonogenicity, differentiation, and egress of their shared myeloid progenitors. Because these same progenitors give rise to osteoclasts (OCs), which also mediate the egress of hematopoietic progenitors and orchestrate bone remodeling, we hypothesized that iNKT cells would extend their myeloid cell regulatory role to the development and function of OCs. In this study, we report that selective activation of iNKT cells by α-galactosylceramide causes myeloid cell egress, enhances OC progenitor and precursor development, modifies the intramedullary kinetics of mature OCs, and enhances their resorptive activity. OC progenitor activity is positively regulated by TNF-α and negatively regulated by IFN-γ, but is IL-4 and IL-17 independent. These data demonstrate a novel role of iNKT cells that couples osteoclastogenesis with myeloid cell egress in conditions of immune activation.


Subject(s)
Cell Differentiation/immunology , Lymphocyte Activation/immunology , Natural Killer T-Cells/cytology , Natural Killer T-Cells/immunology , Osteoclasts/immunology , Osteoclasts/metabolism , Animals , Cell Movement/immunology , Dendritic Cells/cytology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Down-Regulation/immunology , Interferon-gamma/physiology , Macrophage Colony-Stimulating Factor/physiology , Macrophages/cytology , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Myeloid Cells/cytology , Myeloid Cells/immunology , Myeloid Cells/metabolism , Natural Killer T-Cells/metabolism , Osteoclasts/cytology , RANK Ligand/physiology , Stem Cells/cytology , Stem Cells/immunology , Stem Cells/metabolism , Tumor Necrosis Factor-alpha/physiology , Up-Regulation/immunology
3.
Proc Natl Acad Sci U S A ; 107(16): 7604-9, 2010 Apr 20.
Article in English | MEDLINE | ID: mdl-20368437

ABSTRACT

Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3'-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.


Subject(s)
Bone and Bones/metabolism , Iodide Peroxidase/physiology , Osteoblasts/metabolism , Animals , Bone Density , Bone Resorption , Hypothyroidism/pathology , Iodide Peroxidase/metabolism , Mice , Mice, Knockout , Microscopy, Confocal/methods , Microscopy, Electron, Scanning/methods , Models, Biological , Phenotype , Stress, Mechanical , X-Ray Microtomography/methods , Iodothyronine Deiodinase Type II
4.
Arthritis Res Ther ; 11(5): R159, 2009.
Article in English | MEDLINE | ID: mdl-19857267

ABSTRACT

INTRODUCTION: Calcified deposits (CDs) in skin and muscles are common in juvenile dermatomyositis (DM), and less frequent in adult DM. Limited information exists about the microstructure and composition of these deposits, and no information is available on their elemental composition and contents, mineral density (MD) and stiffness. We determined the microstructure, chemical composition, MD and stiffness of CDs obtained from DM patients. METHODS: Surgically-removed calcinosis specimens were analyzed with fourier transform infrared microspectroscopy in reflectance mode (FTIR-RM) to map their spatial distribution and composition, and with scanning electron microscopy/silicon drift detector energy dispersive X-ray spectrometry (SEM/SDD-EDS) to obtain elemental maps. X-ray diffraction (XRD) identified their mineral structure, X-ray micro-computed tomography (microCT) mapped their internal structure and 3D distribution, quantitative backscattered electron (qBSE) imaging assessed their morphology and MD, nanoindentation measured their stiffness, and polarized light microscopy (PLM) evaluated the organic matrix composition. RESULTS: Some specimens were composed of continuous carbonate apatite containing small amounts of proteins with a mineral to protein ratio much higher than in bone, and other specimens contained scattered agglomerates of various sizes with similar composition (FTIR-RM). Continuous or fragmented mineralization was present across the entire specimens (microCT). The apatite was much more crystallized than bone and dentin, and closer to enamel (XRD) and its calcium/phosphorous ratios were close to stoichiometric hydroxyapatite (SEM/SDD-EDS). The deposits also contained magnesium and sodium (SEM/SDD-EDS). The MD (qBSE) was closer to enamel than bone and dentin, as was the stiffness (nanoindentation) in the larger dense patches. Large mineralized areas were typically devoid of collagen; however, collagen was noted in some regions within the mineral or margins (PLM). qBSE, FTIR-RM and SEM/SDD-EDS maps suggest that the mineral is deposited first in a fragmented pattern followed by a wave of mineralization that incorporates these particles. Calcinosis masses with shorter duration appeared to have islands of mineralization, whereas longstanding deposits were solidly mineralized. CONCLUSIONS: The properties of the mineral present in the calcinosis masses are closest to that of enamel, while clearly differing from bone. Calcium and phosphate, normally present in affected tissues, may have precipitated as carbonate apatite due to local loss of mineralization inhibitors.


Subject(s)
Calcinosis/pathology , Myositis/pathology , Adolescent , Child , Child, Preschool , Female , Humans , Imaging, Three-Dimensional , Male , Microscopy, Electron, Scanning , Middle Aged , Spectrometry, X-Ray Emission , Spectroscopy, Fourier Transform Infrared
5.
Mol Endocrinol ; 22(2): 501-12, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17932107

ABSTRACT

By proposing TSH as a key negative regulator of bone turnover, recent studies in TSH receptor (TSHR) null mice challenged the established view that skeletal responses to disruption of the hypothalamic-pituitary-thyroid axis result from altered thyroid hormone (T(3)) action in bone. Importantly, this hypothesis does not explain the increased risk of osteoporosis in Graves' disease patients, in which circulating TSHR-stimulating antibodies are pathognomonic. To determine the relative importance of T(3) and TSH in bone, we compared the skeletal phenotypes of two mouse models of congenital hypothyroidism in which the normal reciprocal relationship between thyroid hormones and TSH was intact or disrupted. Pax8 null (Pax8(-/-)) mice have a 1900-fold increase in TSH and a normal TSHR, whereas hyt/hyt mice have a 2300-fold elevation of TSH but a nonfunctional TSHR. We reasoned these mice must display opposing skeletal phenotypes if TSH has a major role in bone, whereas they would be similar if thyroid hormone actions predominate. Pax8(-/-) and hyt/hyt mice both displayed delayed ossification, reduced cortical bone, a trabecular bone remodeling defect, and reduced bone mineralization, thus indicating that the skeletal abnormalities of congenital hypothyroidism are independent of TSH. Treatment of primary osteoblasts and osteoclasts with TSH or a TSHR-stimulating antibody failed to induce a cAMP response. Furthermore, TSH did not affect the differentiation or function of osteoblasts or osteoclasts in vitro. These data indicate the hypothalamic-pituitary-thyroid axis regulates skeletal development via the actions of T(3).


Subject(s)
Bone Development/physiology , Hypothyroidism/pathology , Paired Box Transcription Factors/physiology , Thyroid Hormones/blood , Thyrotropin/blood , Animals , Blotting, Western , Bone Development/drug effects , Bone Development/genetics , Bone Remodeling/drug effects , Bone Remodeling/genetics , Bone Remodeling/physiology , Bone and Bones/abnormalities , Bone and Bones/metabolism , Calcification, Physiologic/drug effects , Calcification, Physiologic/genetics , Calcification, Physiologic/physiology , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Differentiation/physiology , Cells, Cultured , Cyclic AMP/metabolism , Hypothyroidism/blood , Hypothyroidism/genetics , In Situ Hybridization , Mice , Mice, Knockout , Osteoblasts/cytology , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteoclasts/cytology , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteogenesis/drug effects , Osteogenesis/physiology , PAX8 Transcription Factor , Paired Box Transcription Factors/genetics , Paired Box Transcription Factors/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Thyroid Gland/metabolism , Thyroid Hormones/pharmacology
6.
Mol Endocrinol ; 21(8): 1893-904, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17488972

ABSTRACT

Childhood hypothyroidism delays ossification and bone mineralization, whereas adult thyrotoxicosis causes osteoporosis. To determine how effects of thyroid hormone (T3) during development manifest in adult bone, we characterized TRalpha1(+/m)beta(+/-) mice, which express a mutant T3 receptor (TR) alpha1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TRalpha1(+/m)beta(+/-) mice had osteosclerosis with increased bone mineralization even though juveniles had delayed ossification. This phenotype was partially normalized by transient T3 treatment of juveniles and fully reversed in compound TRalpha1(+/m)beta(-/-) mutant mice due to 10-fold elevated hormone levels that allow the mutant TRalpha1 to bind T3. By contrast, deletion of TRbeta in TRalpha1(+/+)beta(-/ -) mice, which causes a 3-fold increase of hormone levels, led to osteoporosis in adults but advanced ossification in juveniles. T3-target gene analysis revealed skeletal hypothyroidism in TRalpha1(m/+)beta(+/-) mice, thyrotoxicosis in TRalpha1(+/+)beta(-/-) mice, and euthyroidism in TRalpha1(+/)beta(-/-) double mutants. Thus, TRalpha1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization.


Subject(s)
Bone Development/physiology , Bone and Bones/anatomy & histology , Calcification, Physiologic , Thyroid Gland/physiology , Animals , Bone and Bones/cytology , Mice , Mice, Knockout , Thyroid Hormone Receptors alpha/deficiency , Thyroid Hormone Receptors alpha/genetics , Thyroid Hormone Receptors beta/deficiency , Thyroid Hormone Receptors beta/genetics
7.
Mol Endocrinol ; 21(5): 1095-107, 2007 May.
Article in English | MEDLINE | ID: mdl-17327419

ABSTRACT

Thyrotoxicosis is an important but under recognized cause of osteoporosis. Recently, TSH deficiency, rather than thyroid hormone excess, has been suggested as the underlying cause. To investigate the molecular mechanism of osteoporosis in thyroid disease, we characterized the skeleton in mice lacking either thyroid hormone receptor alpha or beta (TRalpha(0/0), TRbeta-/-). Remarkably, in the presence of normal circulating thyroid hormone and TSH concentrations, adult TRalpha(0/0) mice had osteosclerosis accompanied by reduced osteoclastic bone resorption, whereas juveniles had delayed endochondral ossification with reduced bone mineral deposition. By contrast, adult TRbeta-/- mice with elevated TSH and thyroid hormone levels were osteoporotic with evidence of increased bone resorption, whereas juveniles had advanced ossification with increased bone mineral deposition. Analysis of T3 target gene expression revealed skeletal hypothyroidism in TRalpha(0/0) mice, but skeletal thyrotoxicosis in TRbeta-/- mice. These studies demonstrate that bone loss in thyrotoxicosis is independent of circulating TSH levels and mediated predominantly by TRalpha, thus identifying TRalpha as a novel drug target in the prevention and treatment of osteoporosis.


Subject(s)
Hyperthyroidism/physiopathology , Osteoporosis/etiology , Thyroid Hormones/physiology , Thyrotropin/deficiency , Aging , Animals , Animals, Newborn , Bone Density , Bone Resorption/genetics , Bone and Bones/pathology , Bone and Bones/ultrastructure , Embryo, Mammalian , Hyperthyroidism/pathology , Mice , Mice, Knockout , Microscopy, Electron, Scanning , Osteoporosis/genetics , Osteoporosis/pathology , Thyroid Hormone Receptors alpha/deficiency , Thyroid Hormone Receptors alpha/genetics , Thyroid Hormone Receptors beta/deficiency , Thyroid Hormone Receptors beta/genetics , Thyrotropin/physiology
8.
J Prosthet Dent ; 91(1): 26-32, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14739890

ABSTRACT

STATEMENT OF PROBLEM: Edentulous patients treated with implant-supported prostheses have shown increased passive tactile sensibility compared with those using conventional complete dentures. This is thought to be due to the close mechanical coupling between the implant and bone via the osseointegrated interface, yet the phenomenon has received little attention. PURPOSE: The purpose of this study was to measure passive tactile sensibility in a group of edentulous subjects treated with dental implants, and to relate the measured sensibility to a range of factors thought to be of possible relevance, namely, patient age, gender, time since implant placement, implant length, and implant separation. MATERIAL AND METHODS: Twenty edentulous subjects successfully treated with 2 or more Nobel Biocare dental implants in the anterior mandible were studied. The inclusion criteria were : (1) age of less than 50 years, (2) a period of at least 12 months since implant placement, (3) implant length of at least 10 mm and of standard diameter (excluding narrow and wide platform designs), and (4) implant separation of at least 18 mm. Using a computer-controlled custom-made device, pushing forces (2.1, 2.4, 2.7, and 3.0 N/s) were applied directly and perpendicular to the long axes of the implant abutments until the subjects felt the first sensation of pressure. The magnitude of these forces was measured with an integral transducer. The applied force had a ramped staircase pattern, and force application rates were varied between 2.1 and 3.0 N/s. Multilevel modeling was used to analyze the collected data (alpha=.05). RESULTS: The threshold values of passive tactile sensibility ranged between 3.1 and 15.7 N (mean 10.9; SD 3.9). Analysis failed to show any significant association between passive tactile sensibility and the variables studied. CONCLUSION: Within the limitations of this study, which included a small sample size, no relationship was found between passive tactile sensibility associated with long-standing implants and any of the variables studied (age, gender, time since implant placement, implant length, and implant separation).


Subject(s)
Dental Implants , Mouth, Edentulous/physiopathology , Sensory Thresholds/physiology , Touch/physiology , Age Factors , Aged , Aged, 80 and over , Dental Abutments , Dental Prosthesis Design , Dental Prosthesis, Implant-Supported , Female , Humans , Male , Mandible/physiopathology , Middle Aged , Mouth, Edentulous/rehabilitation , Pilot Projects , Pressure , Sex Factors , Stress, Mechanical , Time Factors , Weight-Bearing
9.
J Bone Miner Res ; 18(7): 1235-46, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12854833

ABSTRACT

UNLABELLED: Deposition, mineralization, and resorption of FD bone compared with unaffected bone from FD patients was investigated in iliac crest biopsy specimens from 13 patients. Compared with unaffected bone, lesional FD bone seemed to be very sensitive to the effects of PTH and renal phosphate wasting, which respectively bring about hyperparathyroid or osteomalacic changes in the lesional bone. INTRODUCTION: Fibrous dysplasia is a genetic noninherited disease caused by activating mutations of the GNAS1 gene, resulting in the deposition of qualitatively abnormal bone and marrow. This study was designed to learn more about the local processes of bone deposition, mineralization, and resorption within lesional fibrous dysplasia (FD) bone compared with unaffected bone of FD patients. METHODS: Histology, histomorphometry, and quantitative back-scattered electron imaging (qBSE) analysis was conducted on affected and unaffected biopsy specimens from 13 patients and correlated to markers of bone metabolism. RESULTS AND CONCLUSIONS: There was a marked excess of unmineralized osteoid with a nonlamellar structure and a reduced mineral content in mineralized bone within FD lesions (p < 0.001). A negative correlation (p = 0.05) between osteoid thickness (O.Th) and renal tubular phosphate reabsorption (measured as TmP/GFR) was observed for lesional bone, but not for unaffected bone, in which no histological or histomorphometric evidence of osteomalacia was observed in patients with renal phosphate wasting. Histological and histomorphometric evidence of increased bone resorption was variable in lesional bone and correlated with serum levels of parathyroid hormone (PTH). Hyperparathyroidism-related histological changes were observed in fibrous dysplastic bone, but not in the unaffected bone, of patients with elevated serum PTH secondary to vitamin D deficiency. Our data indicate that, compared with unaffected bone, lesional FD bone is very sensitive to the effects of PTH and renal phosphate wasting, which, respectively, bring about hyperparathyroid or osteomalacic changes in the lesional bone. Osteomalacic and hyperparathyroid changes, which emanate from distinct metabolic derangements (which superimpose on the local effects of GNAS1 mutations in bone), influence, in turn, the severity and type of skeletal morbidity in FD.


Subject(s)
Fibrous Dysplasia of Bone/metabolism , Fibrous Dysplasia of Bone/pathology , Hyperparathyroidism/complications , Osteomalacia/complications , Adolescent , Adult , Biopsy , Bone Resorption , Calcification, Physiologic , Child , Chromogranins , DNA Mutational Analysis , Female , Fibrous Dysplasia of Bone/complications , Fibrous Dysplasia of Bone/genetics , Fibrous Dysplasia, Polyostotic/complications , Fibrous Dysplasia, Polyostotic/genetics , Fibrous Dysplasia, Polyostotic/metabolism , Fibrous Dysplasia, Polyostotic/pathology , GTP-Binding Protein alpha Subunits, Gs/genetics , Humans , Hyperparathyroidism/metabolism , Hyperparathyroidism/pathology , Male , Middle Aged , Osteomalacia/metabolism , Osteomalacia/pathology , Parathyroid Hormone/metabolism
10.
Int J Oral Maxillofac Implants ; 18(2): 266-72, 2003.
Article in English | MEDLINE | ID: mdl-12705306

ABSTRACT

PURPOSE: This study investigated the changes that might occur in passive tactile sensibility during a period of 3 months following Implant placement in a group of edentulous subjects treated with dental implants. The effect of changing the velocity of force application on passive tactile sensibility was also investigated. MATERIALS AND METHODS: Five edentulous subjects who had been treated (as a part of an immediate loading study) with 2 or more Nobel Biocare dental implants in the anterior mandible were studied. Pushing forces were applied directly and perpendicular to the long axes of the abutments until the subjects felt the first sensation of pressure, using a computer-controlled, custom-made device. The force was measured with an integral transducer. The applied force had a ramped staircase pattern, which was used at 2 different tip velocities. The measurements were taken on 4 occasions: 1, 2, 4, and 12 weeks after fitting the abutments. RESULTS: Statistical analysis, using multilevel modeling, demonstrated that there was a significant decrease In the tactile threshold over successive weeks following implant placement. It also demonstrated that high velocity exhibited a higher threshold than low velocity. DISCUSSION AND CONCLUSION: It could be concluded that there was a significant increase In passive tactile sensibility during the healing phase following implant placement.


Subject(s)
Dental Implants , Jaw, Edentulous/physiopathology , Touch , Aged , Dental Abutments , Dental Implantation, Endosseous , Dental Stress Analysis , Female , Humans , Male , Middle Aged , Models, Statistical , Multivariate Analysis , Osseointegration/physiology , Pressure , Reproducibility of Results , Sensory Thresholds , Time Factors
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