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PubMed2002

Percutaneous plating of distal tibial fractures.

This article presents our experience with 24 patients who had distal tibial fractures and were treated by percutaneous plate fixation. Distribution of the fractures according to the AO/OTA classification was as follows: five patients suffered from a 43 A type fracture, six from a 43 B type fracture, and 13 from a 43 C type fractures. Four of the fractures were open. Exclusion criteria included 43 C3 fractures and Gustilo III open fractures. All fractures showed radiographic signs of union enough to enable full weightbearing within an average time of 12.3 weeks. All patients showed a good range of motion (average dorsiflexion 12 degrees and average plantiflexion 18 degrees). Two fractures united with mal-union: one with an 8 degrees valgus deformity and another with a 7 degrees varus deformity. Both cases, which had a metaphyseal component, were treated by means of a "soft" (flexible and manually adjustable) AO 3.5 mm reconstruction plate. Except for one case of superficial infection, no infections were detected in any of the patients. The biological percutaneous plate fixation of distal tibial fractures with no extensive intra-articular involvement is a good soft tissue preserving technique. It provides a rigid and anatomical fixation in most cases. We conclude that type B fractures with one intact column can be fixed with either "soft" or "rigid" plates, and type A and C fractures with a metaphyseal component should be fixed with "rigid" plates (AO 4.5 mm Dynamic Compression Plate). In these fractures the reduction should be performed cautiously due to the tendency of sagittal plane mal-reduction.

Adult↗
PubMed1989

Lateral supporting ligament of the distal phalanx.

A 49-year-old woman complained of 3 months of constant aching pain deep to the ingrown medial nail margin of her right hallux that was unaffected by shoe wear. Physical examination disclosed no purulence, discoloration, or obvious acute inflammation; an incurved medial nail plate was seen. There was mild chronic thickening of the medial nail fold. Tenderness was maximal 2 to 3 mm plantar to the medial edge of the nail. By roentgenogram, bony projections were seen arcing from the distal phalangeal tuft and the proximal metaphyseal flare toward each other. This was considered to be a "normal" radiological variant. A partial medial onychectomy and matricectomy (Winograd procedure) was performed. Further dissection 1 to 2 mm deeper along the medial phalangeal border revealed a 1-mm wide longitudinal ligament extending from the phalangeal distal tuft to the proximal metaphyseal flare. Bony projections and ligament were excised. The wound healed satisfactorily, and symptoms ceased.

Female↗
PubMed1980

Matrix-induced endochondral bone differentiation: influence of hypophysectomy, growth hormone, and thyroid-stimulating hormone.

The influence of hypophysectomy (hypox), GH, and TSH on the discrete phases of matrix-induced endochondral bone differentiation was investigated. [3H]Thymidine incorporation by proliferating mesenchymal cells on day 3 was inhibited by hypox, but was corrected by GH administration. On day 7, 35SO4 incorporation into cartilage proteoglycans was reduced by hypox, but was restored to values higher than controls by GH. Calcification of cartilage and bone was monitored by alkaline phosphatase activity. 45Ca incorporation into bone mineral, and total calcium. Alkaline phosphatase levels were maximal on day 11 in the controls and declined thereafter; however, the activity of alkaline phosphatase remained elevated in hypox recipients. Hypox reduced and delayed the rate and extent of calcification, as reflected by 45Ca incorporation and total calcium, respectively. The administration of GH and TSH alone and in combination restored 45Ca incorporation to control values in tibial metaphyses but not in the matrix-induced osteogenic plaques on day 10. These findings imply that the hormonal requirements for initiation of de novo mineralization of bone may be different from those required for the maintenance of mineralization that was initiated in early fetal life, as in the case of metaphyses. Hypox resulted in a delayed and reduced bone formation due to 1) inhibition of mesenchymal cell proliferation, 2) decreased and delayed chondrogenesis, 3) delayed and reduced vascular invasion, and 4) impaired bone formation.

Acid Phosphatase↗
PubMed2000

Dynamic regulation of RGS2 in bone: potential new insights into parathyroid hormone signaling mechanisms.

The initial steps involved in mediating the transduction of PTH signal via its G protein-coupled receptors are well understood and occur through the activation of cAMP and phospholipase C pathways. However, the cellular and molecular mechanisms for subsequent receptor desensitization are less well understood. Recently, a new family of GTPase activating proteins known as regulators of G protein signaling (RGS), has been implicated in desensitization of several G protein-coupled ligand-induced processes. At present, it is not known whether any of the RGS proteins play a role in PTH signaling. Using the differential display method, we screened for genes that are selectively expressed after a single s.c. injection of human PTH (1-38) (8 microg/100 g) in osteoblast-enriched femoral metaphyseal spongiosa of young male rats (3-4 weeks old). We found and cloned one full-length complementary DNA that encodes a 211-amino acid RGS protein and shares 97% sequence identity with mouse and human RGS2. Based on sequence similarity, we have designated this clone as rat RGS2. Northern blot analysis confirmed that the expression of RGS2 messenger RNA (mRNA) is rapidly and transiently increased by human PTH (1-38) in both metaphyseal (4-to 5-fold) and diaphyseal (2- to 3-fold) bone, as well as in cultured osteoblast cultures (2- to 37-fold). In vitro, forskolin and dibutyryl cAMP similarly elevated RGS2 mRNA. In vivo, PTH analog (1-31) [which stimulates intracellular cAMP accumulation, PTHrP (1-34), and prostaglandin E2] induced RGS2 mRNA expression; whereas PTH analogs (3-34) and (7-34), which do not stimulate cAMP production, had no effect on expression. In tissue distribution analysis, RGS2 is widely expressed and was detected in all tissues examined (heart, spleen, liver, skeletal muscle, kidney, and testis), with significant expression in two nonclassical PTH-sensitive tissues: the brain, and the heart. After PTH injection, RGS2 mRNA expression was induced in rat bone but not in any of the other tissues examined. These findings demonstrate that RGS2 is regulated by PTH, prostaglandin E2, and PTHrP and that regulation by PTH in bone occurs via the cAMP pathway. Additionally, these results suggest the exciting possibility that increased RGS2 expression in osteoblasts may be one of the early events influencing PTH signaling.

Amino Acid Sequence↗
PubMed2000

ADAMTS-1: A cellular disintegrin and metalloprotease with thrombospondin motifs is a target for parathyroid hormone in bone.

PTH stimulates bone formation in animals and humans, and the expressions of a number of genes have been implicated in the mediation of this effect. To discover new bone factors that initiate and support this phenomenon we used differential display RT-PCR and screened for genes that are selectively expressed in osteoblast-enriched femoral metaphyseal primary spongiosa of young male rats after a single s.c. injection of human PTH-(1-38) (8 microg/100 g). We show that one of the messenger RNAs that is up-regulated in bone is ADAMTS-1, a new member of the ADAM (A disintegrin and metalloprotease) gene family containing thrombospondin type I motifs. ADAMTS-1 consists of multiple domains common to ADAM family of proteins, including pro-, metalloprotease-like, and disintegrin-like domains. However, unlike other ADAMs, ADAMTS-1 does not possess a transmembrane or cytoplasmic domain and is a secreted protein. Northern blot analysis confirmed that ADAMTS-1 was up-regulated in both metaphyseal (14- to 35-fold) and diaphyseal (4.2-fold) bone 1 h after PTH-(1-38) injection and returned to control levels by 24 h. We also analyzed the regulation of ADAMTS-1 in response to various PTH/PTH-related peptide (PTHrP) analogs and found that PTH-(1-31) and PTHrP-(1-34), which activate the protein kinase A (PKA) pathway, induce ADAMTS-1 expression 1 h after injection, whereas PTH-(3-34) and PTH-(7-34), which do not activate the PKA pathway, did not regulate expression. To investigate the effect of other osteotropic agents, we analyzed ADAMTS-1 expression after a single dose of PGE2 (6 mg/kg) and found that it was up-regulated 1 h after injection and returned to control levels by 6 h. In vitro ADAMTS-1 is expressed in primary osteoblasts and osteoblastic cell lines, but was not detectable in osteoclasts generated from macrophage colony-stimulating factor/receptor activator of NF-kappaB ligand/transforming growth factor-beta1-treated bone marrow cells. Treatment of UMR 106 osteosarcoma cells with PTH, PGE2, forskolin, or (Bu)2cAMP increased ADAMTS-1 expression 7-, 4-, 5-, and 5-fold, respectively. Also, in vitro treatment with 1alpha,25-dihydroxyvitamin D3 increased ADAMTS-1 expression 3-fold. Tissue distribution analysis showed that ADAMTS-1 is expressed at high levels in many tissues, including the heart, lung, liver, skeletal muscle, and kidney. Taken together, these results demonstrate that ADAMTS-1 is specifically up-regulated in bone and osteoblasts by the osteotropic agents PTH, PTHrP, and PGE2 possibly via the cAMP/PKA pathway. We speculate that the rapid and transient increase in ADAMTS-1 expression may contribute to some of the effects of PTH on bone turnover.

ADAM Proteins↗
PubMed2002

Congenital chondrodysplastic dwarfism with dyshematopoiesis in a holstein calf.

A holstein calf with congenital chondrodysplastic dwarfism was histopathologically examined. The head of the calf was relatively flat giving a dog-like appearance with its short nose and sloping forehead. Limb bones were dumbbell-like with short diaphysis and hypertrophied metaphyses. Bone marrow was pale, whitish and fatty. In the metaphyseal plates most of chondrocytes were pyknotic with swollen and ghost-like cytoplasm, and were irregularly arranged. Column of calcified cartilage were poorly formed losing comb-like structure. Bone marrow was ischemic with poor hematopoiesis and was moderately replaced by adipose tissue. In articular cartilage, most of chondrocytes were degenerated with ghost-like cytoplasm. Many cartilage canals and occasional bone marrow-like structure were formed. The characteristics lesions of the calf were chondrodysplasia and dyshematopoiesis.

Animals↗
PubMed1989

Abnormalities of proximal femoral growth after severe Perthes' disease.

We studied the pattern of proximal femoral growth after severe Perthes' disease (Catterall grade III or IV) by retrospective analysis of serial radiographs in 52 hips (46 patients). Our aim was to determine the relationship between proximal femoral growth abnormalities and metaphyseal cysts, epiphyseal extrusion, physeal narrowing, and extensive epiphyseal necrosis. The average follow-up after treatment was 9.8 years (range 4 to 16 years), and 37 of the hips were followed to skeletal maturity. Slowing of proximal femoral growth was common: symmetrical abnormality was seen in 26 hips and asymmetrical abnormality in nine. However, definite premature closure of the proximal femoral physis was seen in only three hips. Abnormality seemed to be due to altered growth velocity rather than to bar formation in most cases. Metaphyseal cysts, epiphyseal extrusion and physeal narrowing during the active stage of the disease, alone or in combination, were found to be neither sensitive nor specific predictors of the subsequent growth pattern.

Adolescent↗
PubMed1997

The effects of mechanical forces on bones and joints. Experimental study on the rat tail.

We have used an experimental model employing the bent tail of rats to investigate the effects of mechanical forces on bones and joints. Mechanical strain could be applied to the bones and joints of the tail without direct surgical exposure or the application of pins and wires. The intervertebral disc showed stretched annular lamellae on the convex side, while the annulus fibrosus on the concave side was pinched between the inner corners of the vertebral epiphysis. In young rats with an active growth plate, a transverse fissure appeared at the level of the hypertrophic cell layer or the primary metaphyseal trabecular zone. Metaphyseal and epiphyseal trabeculae on the compressed side were thicker and more dense than those of the distracted part of the vertebra. In growing animals, morphometric analysis of hemiepiphyseal and hemimetaphyseal areas, and the corresponding trabecular bone density, showed significant differences between the compressed and distracted sides. No differences were observed in adult rats. We found no significant differences in osteoclast number between compressed and distracted sides in either age group. Our results provide quantitative evidence of the working of 'Wolff's law'. The differences in trabecular density are examples of remodelling by osteoclasts and osteoblasts; our finding of no significant difference in osteoclast numbers between the hemiepiphyses in the experimental and control groups suggests that the response of living bone to altered strain is mediated by osteoblasts.

Age Factors↗
PubMed2005

Exercise-induced strain and strain rate in the distal radius.

Strains applied to bone can stimulate its development and adaptation. High strains and rates of strain are thought to be osteogenic, but the specific dose response relationship is not known. In vivo human strain measurements have been performed in the tibia to try to identify optimal bone strengthening exercises for this bone, but no measurements have been performed in the distal radial metaphysis, the most frequent site of osteoporotic fractures. Using a strain gauged bone staple, in vivo dorsal metaphyseal radial strains and rates of strain were measured in ten female patients during activities of daily living, standard exercises and falls on extended hands. Push-ups and falling resulted in the largest compression strains (median 1345 to 3146 microepsilon, equivalent to a 0.1345% to 0.3146% length change) and falling exercises in the largest strain rates (18582 to 45954 microepsilon/s). On the basis of their high strain and/or strain rates these or variations of these exercises may be appropriate for distal radial metaphyseal bone strengthening.

Activities of Daily Living↗
PubMed2004

Increase of both angiogenesis and bone mass in response to exercise depends on VEGF.

UNLABELLED: Physiological angiogenesis during bone remodeling is undefined. Treadmill-running rats displayed bone marrow angiogenesis concomitant with bone formation increase and resorption decrease and upregulation of VEGF and its R1 receptor mRNA in proximal tibia. VEGF blockade over 5 weeks of training fully prevented the exercise-induced bone mass gain. INTRODUCTION: We investigated the role of vascular endothelial growth factor (VEGF) and angiogenesis in the osteogenic response to exercise. MATERIALS AND METHODS: Nine-week-old male Wistar rats were treadmill-trained at 60% Vo(2max) for various periods. Bone and vascular histomorphometry was performed after 2- and 5-week experiments. On-line RT PCR for VEGF and its receptors R1 and R2 was done after a 10-day experiment. In the 5-week experiment, running rats received either a VEGF inhibitory antibody or a placebo. RESULTS: After 2 weeks, tibial BMD did not change; however, vessel number in the proximal metaphysis increased by 20% in running versus sedentary rats. In running rats, vessel number correlated positively (r = 0.88) with bone formation rate and negatively (r = -0.85) with active resorption surfaces. After 10 days of training, upregulation of VEGF and VEGF receptor R1 mRNA was detected in periosteum and metaphyseal bone. VEGF blockade in 5-week trained rats fully prevented the exercise-induced increase in metaphyseal BMD (9%) and cancellous bone volume (BV/TV; 25%), as well as the increased vessel number (25%). In 5-week placebo-treated running rats, bone formation rate returned to initial values, whereas osteoclastic surfaces continued to decline compared with both sedentary and anti-VEGF-treated running rats. CONCLUSION: VEGF signaling-mediated bone angiogenesis is tightly related to exercise-induced bone cellular uncoupling and is indispensable for bone gain induced by exercise.

Animals↗
PubMed2004

Chondrocyte-specific knockout of the G protein G(s)alpha leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation.

UNLABELLED: G(s)alpha is a ubiquitously expressed G protein alpha-subunit that couples receptors to adenylyl cyclase. Mice with chondrocyte-specific ablation of the G(s)alpha gene had severe epiphyseal and growth plate abnormalities and ectopic cartilage formation within the metaphyseal region of the tibia. These results show that G(s)alpha negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTH-rP receptor in growth plate chondrocytes. INTRODUCTION: G(s)alpha is a ubiquitously expressed G protein alpha-subunit that mediates signaling through G protein-coupled receptors to activate the cAMP/protein kinase A signaling pathway. Although studies suggest an important role for G(s)alpha in regulating growth plate development, direct in vivo results examining this role are lacking. MATERIALS AND METHODS: The G(s)alpha gene was ablated in murine cartilage by mating mice with loxP sites surrounding the G(s)alpha promoter and first exon with collagen 2a1 promoter-Cre recombinase transgenic mice. Skeletal tissues were studied by gross and microscopic pathology, and gene expression was determined by in situ hybridization. RESULTS AND CONCLUSIONS: Mice with complete chondrocyte-specific G(s)alpha deficiency (homozygotes) died within minutes after birth and had severe epiphyseal and growth plate defects with shortening of the proliferative zone and accelerated hypertrophic differentiation of growth plate chondrocytes, a phenotype similar to that of PTH/PTH-related peptide (PTHrP) receptor knockout mice. Indian hedgehog and PTH/PTHrP receptor expression in prehypertrophic chondrocytes was unaffected in mutant mice. PTHrP expression in periarticular cartilage was increased in the mutant mice, probably because of the closer proximity of Ihh-secreting chondrocytes to the periarticular zone. In addition, these mice developed ectopic cartilage at the anterior side of the metaphyseal region in the tibia. Mice with partial G(s)alpha deficiency (heterozygotes) exhibited no phenotype. These results show that G(s)alpha negatively regulates chondrocyte differentiation and is the critical signaling mediator of the PTH/PTHrP receptor in epiphyseal and growth plate chondrocytes.

Animals↗
PubMed1997

Efferent targets of osseous CGRP-immunoreactive nerve fiber before and after bone destruction in adjuvant arthritic rat: an ultramorphological study on their terminal-target relations.

We report the ultramorphological characterization of the terminal-target relation of sensory peptidergic nerve fibers in healthy and diseased osseous tissues. Bone tissue sections were immunoelectronmicroscopically investigated for calcitonin gene-related peptide (CGRP), a neuropeptide widely distributed in sensory peptidergic fibers. Ultramorphological relation of the osseous CGRP-immunoreactive (ir) nerve terminals and their target cells was comparatively analyzed using healthy, arthritic, and postarthritic bone specimens from control and adjuvant-induced arthritic rats. Terminal-like profiles of the osseous CGRP-ir axons were evidenced in direct contact with the metaphyseal osteoblasts and osteoclasts of the control animals. Terminal-like profiles were also noted in the vicinity of the periosteal lining cells. Nonterminal-like profiles did not make intimate spatial relation to the cells/structures surrounding the nerve. Osseous CGRP-ir terminals and axons, which are either uncovered or thinly ensheathed by the supportive tissues, were extensively degenerated in adjuvant-induced infiltration, whereas larger fibers were relatively resistant. Numerous CGRP-ir axons with distinctive features reinnervated the postarthritic, ossifying periosteum. CGRP-ir axons appeared to reinnervate the eroded surface of metaphyseal bone and cartilage as early as the recruited osteoblasts resume osteogenesis in the postarthritic metaphysis. The observed terminal-target relations in the healthy and diseased bone tissues give an ultramorphological basis for the putative trophic, modulatory actions of CGRP innervation of the bone cells.

Animals↗
PubMed2001

Amylin and bone metabolism in streptozotocin-induced diabetic rats.

Amylin (AMY) is a 37 amino acid peptide cosecreted with insulin (INS) by pancreatic beta-cells and absent in type 1 diabetes, a condition frequently associated with osteopenia. AMY binds to calcitonin receptors, lowers plasma calcium concentration, inhibits osteoclast activity, and stimulates osteoblasts. In the present study, we examined the effects of AMY replacement on bone loss in a streptozotocin (STZ)-induced rodent model type 1 diabetes. Of 50 male Wistar rats studied, 40 were made diabetic with intraperitoneal STZ (50 mg/kg; plasma glucose concentrations > 11 mM within 5 days). Ten nondiabetic control (CONT) rats received citrate buffer without STZ. Diabetic rats were divided into four groups (n = 10/group) and injected subcutaneously with rat AMY (45 mg/kg), INS (12 U/kg), both (same doses), or saline (STZ; diabetic controls) once per day. After 40 days of treatment and five 24-h periods of urine collection for deoxypyridinoline (DPD), the animals were killed, blood was sampled, and femurs were removed. The left femur was tested for mechanical resistance (three-point bending). The right femur was tested for total, diaphyseal (cortical bone), and metaphyseal (trabecular bone) bone densities using dual-energy X-ray absorptiometry (DXA). Bone was ashed to determine total bone mineral (calcium) content. None of the treatments had any significant effect on femoral length and diameter. Untreated diabetic rats (STZ; 145+/-7N) had lower bone strength than did nondiabetic CONT (164+/-38; p < 0.05). Total bone mineral density (BMD; g/cm2) was significantly lower in STZ (0. 2523+/-0.0076) than in CONT (0.2826+/-0.0055), as were metaphyseal and diaphyseal densities. Diabetic rats treated with AMY, INS, or both had bone strengths and bone densities that were indistinguishable from those in nondiabetic CONT. Changes in bone mineral content paralleled those for total BMD (T-BMD). Plasma osteocalcin (OC) concentration, a marker for osteoblastic activity, was markedly lower in untreated diabetic rats (7. 6+/-0.9 ng/ml); p < 0.05) than in nondiabetic CONT (29.8+/-1.7; p < 0.05) or than in AMY (20.1+/-0.7; p < 0.05). Urinary DPD excretion, a marker for bone resorption, was similar in untreated and AMY-treated diabetic rats (35.0+/-3.1 vs. 35.1+/-4.4 nmol/mmol creatinine), intermediate in rats treated with INS (49.9+/-2.7), and normalized in diabetic rats treated with both agents (58.8+/-8.9 vs. 63.2+/-4.5 in CONT). Thus, in our STZ rat model of diabetic osteopenia, addition of AMY improved bone indices apparently by both inhibiting resorption and stimulating bone formation.

Amyloid↗
PubMed2003

Repetitive, negligible force reaching in rats induces pathological overloading of upper extremity bones.

UNLABELLED: Work-related repetitive motion disorders are costly. Immunohistochemical changes in bones resulting from repetitive reaching and grasping in 17 rats were examined. After 3-6 weeks, numbers of ED1+ macrophages and osteoclasts increased at periosteal surfaces of sites of muscle and interosseous membrane attachment and metaphyses of reach and nonreach forelimbs. These findings indicate pathological overloading leading to inflammation and subsequent bone resorption. INTRODUCTION: Sixty-five percent of all occupational illnesses in U.S. private industry are attributed to musculoskeletal disorders arising from the performance of repeated motion, yet the precise mechanisms of tissue pathophysiology have yet to be determined for work-related musculoskeletal disorders. This study investigates changes in upper extremity bone tissues resulting from performance of a voluntary highly repetitive, negligible force reaching and grasping task in rats. MATERIALS AND METHODS: Seventeen rats reached an average of 8.3 times/minute for 45-mg food pellets for 2 h/day, 3 days/week for up to 12 weeks. Seven rats served as normal or trained controls. Radius, ulna, humerus, and scapula were collected bilaterally as follows: radius and ulna at 0, 3, 4, 5, 6, and 12 weeks and humerus and scapula at 0, 4, and 6 weeks. Bones were examined for ED1-immunoreactive mononuclear cells and osteoclasts. Double-labeling immunohistochemistry was performed for ED1 (monocyte/macrophage lineage cell marker) and TRACP (osteoclast marker) to confirm that ED1+ multinucleated cells were osteoclasts. Differences in the number of ED1+ cells over time were analyzed by ANOVA. RESULTS: Between 3 and 6 weeks of task performance, the number of ED1+ mononuclear cells and osteoclasts increased significantly at the periosteal surfaces of the distal radius and ulna of the reach and nonreach limbs compared with control rats. These cells also increased at periosteal surfaces of humerus and scapula of both forelimbs by 4-6 weeks. These cellular increases were greatest at muscle attachments and metaphyseal regions, but they were also present at some interosseous membrane attachments. The number of ED1+ cells decreased to control levels in radius and ulna by 12 weeks. CONCLUSIONS: Increases in ED1+ mononuclear cells and osteoclasts indicate that highly repetitive, negligible force reaching causes pathological overloading of bone leading to inflammation and osteolysis of periosteal bone tissues.

Animals↗
PubMed2005

Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.

Cartilage-hair hypoplasia (CHH) is a pleiotropic disease caused by recessive mutations in the RMRP gene that result in a wide spectrum of manifestations including short stature, sparse hair, metaphyseal dysplasia, anemia, immune deficiency, and increased incidence of cancer. Molecular diagnosis of CHH has implications for management, prognosis, follow-up, and genetic counseling of affected patients and their families. We report 20 novel mutations in 36 patients with CHH and describe the associated phenotypic spectrum. Given the high mutational heterogeneity (62 mutations reported to date), the high frequency of variations in the region (eight single nucleotide polymorphisms in and around RMRP), and the fact that RMRP is not translated into protein, prediction of mutation pathogenicity is difficult. We addressed this issue by a comparative genomic approach and aligned the genomic sequences of RMRP gene in the entire class of mammals. We found that putative pathogenic mutations are located in highly conserved nucleotides, whereas polymorphisms are located in non-conserved positions. We conclude that the abundance of variations in this small gene is remarkable and at odds with its high conservation through species; it is unclear whether these variations are caused by a high local mutation rate, a failure of repair mechanisms, or a relaxed selective pressure. The marked diversity of mutations in RMRP and the low homozygosity rate in our patient population indicate that CHH is more common than previously estimated, but may go unrecognized because of its variable clinical presentation. Thus, RMRP molecular testing may be indicated in individuals with isolated metaphyseal dysplasia, anemia, or immune dysregulation.

Animals↗
PubMed1999

Skeletal resistance to 1,25-dihydroxyvitamin D3 in osteopetrotic rats.

The osteopetrotic (op/op) rat mutation is a lethal mutation in which decreased osteoclast function (bone resorption) coexists with markedly elevated serum levels of 1 ,25-dihydroxyvitamin D3[1,25(OH)2D3]. Increased circulating levels of 1,25(OH)2D3 have been reported in other osteopetrotic animal mutations and in some osteopetrotic children. This study examined the effects of 1,25(OH)2D3 infusions on serum and skeletal parameters in normal and mutant rats of op stock. We also examined vitamin D receptor expression and binding in bone cells from op normal and mutant animals. Four-week-old normal and mutant rats were infused either with propylene glycol (used as controls) or with 12.5-125 ng of 1,25(OH)2D3/d using osmotic minipumps implanted subcutaneously for 1 wk. Sera were analyzed for calcium, phosphorus, and 1,25(OH)2D3 levels. Histomorphometric analyses of proximal tibiae from treated normal (50 ng/d) and op mutant (125 ng/d) rats and their vehicle-infused controls were performed. Normal animals infused with 1,25(OH)2D3 exhibited a dose-dependent increase in serum calcium levels. Histomorphometric analyses of metaphyseal bone within the primary spongiosae region showed that 1,25(OH)2D3 increased osteoclast number with a reduction in osteoblast surface associated with a decrease in growth plate cartilage thickness. However, similar analyses on secondary spongiosae showed a decrease in osteoclast number and surface associated with an anabolic response. Op mutants infused with 1,25(OH)2D3 did not exhibit any change in serum calcium levels or histomorphometric parameters related to growth plate cartilage and metaphyseal bone compared with mutant controls. Vitamin D mRNA and protein levels were increased twoto threefold in op mutants compared to age-matched normal rats. However, binding affinity of 1,25(OH)2D3 to its receptor was similar between op mutant and normal animals. High dose calcitriol therapy, under the conditions and period of treatment used in this study, failed to stimulate bone turnover in op rats, suggesting that they are resistant to the skeletal effects of 1,25(OH)2D3. The failure of osteoclast activation in response to 1,25(OH)2D3 treatment may be associated with osteoblast incompetence in this mutation.

Animals↗
PubMed2004

Atorvastatin enhances bone density in ovariectomized rats given 17beta-estradiol or human parathyroid hormone(1-34).

We investigated the in vivo effect of atorvastatin on bone mineral density (BMD) in ovariectomized (OVX) rats. Eight-week-old female rats underwent either a sham operation or ovariectomy, and treatments with vehicle, atorvastatin, 17beta-estradiol (E2) and human parathyroid hormone(1-34) [hPTH(1-34)] were initiated 6 wk after the surgery. E2 (10 microg/kg) treatment for 12 wk significantly increased lumbar BMD (L2-L4), whereas atorvastatin did not affect lumbar BMD. The combination of atorvastatin (2 mg/kg) and E2 significantly enhanced the BMD of lumbar vertebrae (L2-L4) and femoral metaphyseal area (2/10-4/10 segments from the most proximal point) compared to that of either E2 or atorvastatin alone. A low dose 1 micro g/kg of hPTH (1-34) did not alter lumbar or femoral BMD, whereas a high dose 17.5 micro g/kg of the peptide significantly increased BMD. Concomitant injections of atorvastatin (2 mg/kg) with hPTH(1-34) (1 microg/kg) for 8 wk significantly enhanced the BMD of lumbar vertebrae and the metaphyseal area of the femur in OVX rats. These findings demonstrate that chronic administration of atorvastatin appears to modestly enhance the BMD of the lumbar vertebrae and femoral metaphysis of OVX rats treated with submaximal doses of E2 and hPTH(1-34).

Animals↗
PubMed2000

No influence of osteoarthritis of the hand on phalangeal osteography in elderly women.

We investigate the influence of hand osteoarthritis on skeletal quantitative ultrasound (QUS) measurement through the proximal phalanges in female geriatric inpatients. In a cross-sectional study, bone status was assessed with QUS at the distal metaphysis of the first phalanges of fingers II-V. Thirty-three of 101 female geriatric inpatients met the clinical criteria of the American College of Rheumatology for osteoarthritis of the hands (median age: 85 years) and were compared to 68 female inpatients without swellings of the small finger joints (median age: 88 years). Amplitude-dependent speed of sound at the distal metaphysis, the electronic signal of the ultrasonic wave after crossing the phalanx (graphic trace), and the thickness of the each phalanx were measured and compared between the two groups by a phalangeal QUS device (DBM-Sonic 1200). There were no significant differences between the phalangeal QUS readings of both groups. The only statistically significant difference was observed in the comparison of the small finger thickness with a lower value in the osteoarthritis group (p = 0.02). These findings suggest that at the metaphyseal level of phalanges, the degenerative process of osteoarthritis doesn't influence the QUS assessment. This could be explained by the finger thickness at metaphyseal level, which was not increased in patients with osteoarthritis compared with control subjects, at least as detected by the applied finger ultrasound method.

Aged↗