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Biomedical subjects

M Priemel

Publications and source records attributed to M Priemel.

At least 19 recordsLinked to original sources
PubMed2006

[Pathophysiology and pathomorphology of osteoporosis].

Osteoporosis is a disease that leads to fragility fractures due to loss of bone mass and bone microstructure. This review presents an update on the fundamental pathophysiologic and pathomorphologic mechanisms of bone loss situations. Pathomorphologic characteristics such as perforations and microcallus formations are explained. The physiologic relevance of the remodeling process as well as its control by local-paracrine, systemic-endocrine and central-neural signaling pathways is discussed. Furthermore the role of hormones such as estrogen, FSH and leptin, of transcription-factors such as Runx2 and osterix and as well as that of the wnt signaling pathway for bone cell differentiation and function is presented. On the basis of current knowledge osteoporosis can be diagnosed, treated and fractures can be prevented. However, it is likely that new and even more effective diagnostic and therapeutic strategies will emerge as our understanding of the remodeling process that controls osteoblast and osteoclast function increases.

Bone Resorption↗
PubMed2004

Can geometry-based parameters from pQCT and material parameters from quantitative ultrasound (QUS) improve the prediction of radial bone strength over that by bone mass (DXA)?

The diagnosis of osteoporosis is generally based on the assessment of bone mineral content with dual X-ray absorptiometry (DXA) but does not account for the spatial distribution and inherent material properties of the tissue. Peripheral quantitative computed tomography (pQCT) permits one to measure the compartment-specific density and geometry-based parameters of cortical bone. Quantitative ultrasound (QUS) parameters are associated with material properties of cortical bone. The purpose of this study was to test the hypothesis that pQCT and cortical QUS provide additional information to DXA in predicting structural strength of the distal radius. The intact right arm and the isolated left radius were harvested from 70 formalin-fixed cadavers (age 79+/-11 years). The bone mineral content (BMC) was assessed with DXA at the radial metaphysis and shaft. pQCT was also used at the metaphysis and the shaft, while QUS was employed only at the shaft. The failure loads of the radius were assessed by use of a 3-point bending test (isolated radius) and a complex fall simulation (intact arm). The BMC (DXA) displayed a correlation of r=0.96 with the failure moments in 3-point bending ( P<0.001). The correlation between failure load and geometry-based parameters (pQCT) ranged from r=0.85 to r=0.96 and was r=0.64 for the speed of sound (QUS) ( P <0.001). Cortical thickness (pQCT) improved the prediction marginally (r=0.964) in combination with DXA. For the fall simulation, the correlation coefficients were r=0.76 for BMC (DXA) of the shaft, r=0.83 for metaphyseal bone content (pQCT), r=0.55 for QUS, and ranged from r=0.59 to r=0.74 for geometry-based parameters at the shaft (pQCT). pQCT and QUS parameters provided no significant improvement versus DXA alone. Measurement of bone mass by DXA or pQCT thus appears to be sufficient as a surrogate of mechanical strength and fracture risk of the distal radius.

Absorptiometry, Photon↗
PubMed2004

[Simple bone cysts of the calcaneus. Differential diagnosis and therapy].

Fifty-two calcaneal simple bone cysts from our clinic were evaluated. The lesions had a pathognomonic radiologic appearance and diagnosis was histologically confirmed in all operatively treated cases. Four cases presented with pathological fractures, three of which were treated by open reduction internal fixation and bone grafting, while one was treated nonoperatively. In addition, six patients with large cysts without apparent fracture but spontaneous pain were treated by curettage and subsequent autogenous bone grafting or calcium phosphate cement filling, and there were no recurrences. The majority of cysts (42 of 52) were however asymptomatic and thus followed up nonoperatively. This review reports on one of the largest series of cysts in this location. The results indicate that nonoperative management is justified in most asymptomatic cases. However, the potential risk of fracture as indicated by four fractured calcaneal cysts in this series suggests that large cysts should be clinically monitored and that operative intervention is useful in all symptomatic cases to prevent pathologic fractures. In the latter cases, curettage and bone grafting as well as the use of bone substitute material yielded uniformly good results.

Adolescent↗
PubMed2004

[Evaluation of experimental cartilage lesions with ultrahigh-resolution multi-slice-CT in comparison to histology].

PURPOSE: Histologic validation of ultrahigh-resolution multi-slice (MS)-CT for the evaluation of focal, experimental cartilage lesions with special regard to the subchondral bone. Testing of micro-CT ( micro CT) as alternative reference standard. METHODS: 32 experimental cartilage lesions in bovine patellae were imaged surrounded by air (MS-CT-air) and immersed in a contrast material solution (MS-CT-CM) with MS-CT (collimation 2 x 0,5 mm). After the micro CT (8 micro m-voxelsite) examination in three specimen and histologic work-up of 29 specimen two radiologist graded the defects on MS-CT images in consensus (subchondral bone involvement yes or no) and results were compared to the results of histomorphometry and micro CT. RESULTS: The MS-CT-air and -CM had an accuracy of 94 % (30/32) and 88 % (28/32), respectively. MS-CT-air led to one false-positive (remaining cartilage: = 0,1 mm) and false-negative result, each. MS-CT-CM showed false-positive results if the remaining cartilage was < 0,3 mm thick (n = 4), i. e. showed subchondral bone involvement. Contrast-to-noise ratio was significantly higher in MS-CT-air compared to MS-CT-CM. micro CT yielded a clear depiction of cartilage defect depth in the three cases. CONCLUSION: MS-CT-air has a high accuracy in the depiction of focal cartilage defects. MS-CT-CM has a tendency to overestimate cartilage defect depth. micro CT could potentially serve as alternative reference standard to histology.

Animals↗
PubMed2003

[Treatment of metaphyseal bone defects after fractures of the distal radius. Medium-term results using a calcium-phosphate cement (BIOBON)].

PROBLEM: Since 1998 the calcium-phosphate cement BIOBON has been an established tool for the operative treatment of metaphyseal bone defects. No data are currently available in the literature on the clinical results of employing BIOBON: METHODS: For the evaluation of the mediumterm outcome in the therapy of metaphyseal bone defects after distal radial fractures, we examined 29 patients in a retrospective study. These patients with unstable radial fractures were treated between 1998 and 2001 with BIOBON and additional osteosynthesis. RESULTS: We performed a clinical and radiological examination of 20 patients (69.0%) after an average period of 18.35 months (9-40 months). In all patients parts of the bone replacement material were still visible radiologically. The average outcome using the Gartland and Werley score was 7.5 points (2-21) and therefore a good result. CONCLUSION: Calcium-phosphate cements represent a good alternative to autogenous bone transplantation, especially in elderly patients.

Aged↗
PubMed2002

Osteopenic mice: animal models of the aging skeleton.

While our understanding of the developmental biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics, we still know very little, in molecular and genetic terms, about skeletal physiology. Thus, among the many questions that are largely unexplained are the following: why is osteoporosis mainly a women's disease? How is bone mass maintained nearly constant between the end of puberty and the arrest of gonadal functions? Molecular genetics has emerged as a powerful tool to study previously unexplored aspects of the physiology of the skeleton. Among mammals, mice are the most promising animals for this experimental work. This has been previously demonstrated e.g. through the tremendous impact of the different osteopetrotic models on our molecular understanding of osteoclastic bone resorption. Until recently the only way of studying bone loss situations and osteoporosis in mice was by using ovariectomy with all its limitations. Today, however, we have access to more sophisticated osteoporotic mouse-models from four different origins: Transgenic mice (HSV-TK), knock-out mice (OPG), inbred-strains (SAMP6), and through physiological modulation (icv application). These new models have already taught us several important lessons. The first is, that bone remodeling is more than just an autocrine/paracrine process. Multiple experimental evidence has demonstrated that the latter regulation exists, but genetics prove that there is no functional cross-control between resorption and formation. The second lesson is, that remodeling is, at least in part, subject to central regulation. Thus, osteoporosis is partly a central or hypothalamic disease. However, the most dramatic change and the most important advantage we feel is, that today we have models to test a new hypothesis regarding the etiology of osteoporosis before it turns to dogma. Taken together, mouse-studies may lead to a shift in our physiological understanding of skeleton biology and to the emergence of novel paradigms. These, in turn, should help us to devise new treatments for degenerative diseases of the skeleton such as osteoporosis and its associated clinical problems.

Journal Article↗
PubMed2001

Transgenic and knock out mice in skeletal research. Towards a molecular understanding of the mammalian skeleton.

Our understanding of the biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics. Among mammals, mice are the most promising animals for this experimental work. Because extensive genetic information exists, many mouse mutations are known, and cells from early mouse developmental stages are accessible, scientists have developed transgenic mice - mice in which a gene is introduced or ablated in the germ line. Thus far, we have analyzed more than 100 different transgenic and knock out models with various skeletal phenotypes, covering the major aspects of both skeletal development and skeletal maintenance. Based on these results we here present a first perspective on transgenic and gene knock out animals in skeletal research, including insights in signaling pathways controlling endochondral bone formation, in the regulation of osteoblast function, osteoclastic bone resorption and in bone tumorigenesis, as well as the central control of bone formation. The use of transgenic mice to dissect and analyze regulatory mechanisms in bone cell physiology and the pathogenesis of human bone diseases is an extremely powerful experimental tool. The data presented here demonstrate that the successful convergence of novel genetic approaches with the established and fundamental knowledge of bone biology has made a beginning.

Journal Article↗
PubMed2000

Genetic ablation of parathyroid glands reveals another source of parathyroid hormone.

The parathyroid glands are the only known source of circulating parathyroid hormone (PTH), which initiates an endocrine cascade that regulates serum calcium concentration. Glial cells missing2 (Gcm2), a mouse homologue of Drosophila Gcm, is the only transcription factor whose expression is restricted to the parathyroid glands. Here we show that Gcm2-deficient mice lack parathyroid glands and exhibit a biological hypoparathyroidism, identifying Gcm2 as a master regulatory gene of parathyroid gland development. Unlike PTH receptor-deficient mice, however, Gcm2-deficient mice are viable and fertile, and have only a mildly abnormal bone phenotype. Despite their lack of parathyroid glands, Gcm2-deficient mice have PTH serum levels identical to those of wild-type mice, as do parathyroidectomized wild-type animals. Expression and ablation studies identified the thymus, where Gcm1, another Gcm homologue, is expressed, as the additional, downregulatable source of PTH. Thus, Gcm2 deletion uncovers an auxiliary mechanism for the regulation of calcium homeostasis in the absence of parathyroid glands. We propose that this backup mechanism may be a general feature of endocrine regulation.

Animals↗
PubMed2000

Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass.

Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.

Animals↗
PubMed2000

Progressive increase in bone mass and development of odontomas in aging osteopetrotic c-src-deficient mice.

The critical role of c-src in osteoclast-mediated bone resorption has been emphasized by gene deletion experiments in mice. However, the long-term effects of the lack of c-src and impaired osteoclast function on the skeleton remain unknown. To further study the physiological role of c-src and to circumvent the early death of src(-/-) mice, due to starvation in the absence of erupted teeth, we maintained mice on a liquid diet. At the age of 2 months the src(-/-) mice presented signs of airway obstruction and all mice died progressively between 2.5 and 6 months of age. Radiography demonstrated severe osteopetrosis of the whole skeleton. Histomorphometrical analysis of the src(-/-) mice confirmed a significant increase in bone mass with age, resulting in complete loss of bone marrow spaces in some bones and explaining the consistent hepatosplenomegaly, due to extraskeletal hematopoesis. Histopathological examination of the skull revealed the presence of odontomas in the region of the unerupted incisors, with a penetrance of 100% in the aging src(-/-) mice. Although odontomas are benign lesions, their progressive growth leads to the obliteration of the nasal airways, progressive suffocation, and death in src(-/-) mice. These results suggest that: (i) in the absence of bone resorption, bone formation continues and leads to progressive accentuation of the osteopetrotic phenotype in src(-/-) mice; (ii) osteoclastic function is required for regular eruption of the incisors and deficient bone resorption is associated with the development of odontomas; and (iii) src(-/-) mice die by suffocation due to airway obliteration as a result of progressive odontoma growth.

Aging↗
PubMed2000

Osteopenia and decreased bone formation in osteonectin-deficient mice.

Bone continuously remodels in response to mechanical and physiological stresses, allowing vertebrates to renew bone as adults. Bone remodeling consists of the cycled synthesis and resorption of collagenous and noncollagenous extracellular matrix proteins, and an imbalance in this process can lead to disease states such as osteoporosis, or more rarely, osteopetrosis. There is evidence that the extracellular matrix glycoprotein osteonectin or secreted protein acidic and rich in cysteine (BM-40) may be important in bone remodeling. Osteonectin is abundant in bone and is expressed in areas of active remodeling outside the skeleton. In vitro studies indicate that osteonectin can bind collagen and regulate angiogenesis, metalloproteinase expression, cell proliferation, and cell-matrix interactions. In some osteopenic states, such as osteogenesis imperfecta and selected animal models for bone fragility, osteonectin expression is decreased. To determine the function of osteonectin in bone, we used contact x-ray, histomorphometry, and Northern blot analysis to characterize the skeletal phenotype of osteonectin-null mice. We found that osteonectin-null mice have decreased bone formation and decreased osteoblast and osteoclast surface and number, leading to decreased bone remodeling with a negative bone balance and causing profound osteopenia. These data indicate that osteonectin supports bone remodeling and the maintenance of bone mass in vertebrates.

Animals↗
PubMed1999

A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development.

The molecular mechanisms controlling bone extracellular matrix (ECM) deposition by differentiated osteoblasts in postnatal life, called hereafter bone formation, are unknown. This contrasts with the growing knowledge about the genetic control of osteoblast differentiation during embryonic development. Cbfa1, a transcriptional activator of osteoblast differentiation during embryonic development, is also expressed in differentiated osteoblasts postnatally. The perinatal lethality occurring in Cbfa1-deficient mice has prevented so far the study of its function after birth. To determine if Cbfa1 plays a role during bone formation we generated transgenic mice overexpressing Cbfa1 DNA-binding domain (DeltaCbfa1) in differentiated osteoblasts only postnatally. DeltaCbfa1 has a higher affinity for DNA than Cbfa1 itself, has no transcriptional activity on its own, and can act in a dominant-negative manner in DNA cotransfection assays. DeltaCbfa1-expressing mice have a normal skeleton at birth but develop an osteopenic phenotype thereafter. Dynamic histomorphometric studies show that this phenotype is caused by a major decrease in the bone formation rate in the face of a normal number of osteoblasts thus indicating that once osteoblasts are differentiated Cbfa1 regulates their function. Molecular analyses reveal that the expression of the genes expressed in osteoblasts and encoding bone ECM proteins is nearly abolished in transgenic mice, and ex vivo assays demonstrated that DeltaCbfa1-expressing osteoblasts were less active than wild-type osteoblasts. We also show that Cbfa1 regulates positively the activity of its own promoter, which has the highest affinity Cbfa1-binding sites characterized. This study demonstrates that beyond its differentiation function Cbfa1 is the first transcriptional activator of bone formation identified to date and illustrates that developmentally important genes control physiological processes postnatally.

Amino Acid Sequence↗
PubMed1999

[Gorham-Stout idiopathic osteolysis--a local osteoclastic hyperactivity?].

One rare case of so-called massive idiopathic osteolysis Gorham-Stout is presented. In a 77-year-old female patient the whole right femoral head and neck of femur was resorbed within 2.5 month following trauma. As a histologic cause for the osteolysis, a marked stimulation of osteoclasts on the spongiosa, especially intracortically, was observed. The course and the clinical findings are described, and the pathogenesis and treatment are discussed in comparison with the present literature. The results suggest that an early antiresorptive therapy (calcitonin, bisphosphonates) could stop the progressive osteolytic changes.

Aged↗
PubMed1999

[Chondromyxoid fibroma. Morphological variations, site, incidence, radiologic criteria and differential diagnosis].

Chondromyxoid fibroma is a rare benign bone tumor, accounting for less than 1% of all bone tumors. The peak age incidence is the second and third decade of life. Chondromyxoid fibrom occurs in the metaphyseal parts of the major tubular bones, predominantly of the lower extremity. Roentgenograms show, in most cases, a well-demarcated radiolucent lesion. The classic histological feature of a chondromyxoid fibroma is stellate or spindle-shaped cells arranged in lobules in a myxoid or chondroid background. Analysis of 40 chondromyxoid fibromas demonstrates the morphological variation of this tumor. Cases were examined for age distribution, localization, and radiological and histological features. In 85% we found the typical histomorphological pattern. Recurrence rate was 12.5%. In four cases the appearance was uncharacteristic and differentiation from other tumors such as chondroblastoma or chondrosarcoma was quite difficult. By adhering to strict histomorphological criteria, definite diagnosis of chondromyxoid fibroma can be made in most cases.

Adolescent↗
PubMed1999

Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses.

1,25-Dihydroxyvitamin D3 has been shown to play an important role in vitro in regulating osteoblast gene transcription and promoting osteoclast differentiation. To address the role of the vitamin D receptor (VDR) in skeletal homeostasis, formal histomorphometric analyses were performed in VDR null mice in the setting of impaired mineral ion homeostasis as well as in VDR null mice in whom normal mineral ion homeostasis had been preserved. In hypocalcemic VDR null mice, there was an increase in bone volume as a result of a dramatic increase in osteoid. There was also an increase in the number of osteoblasts without a significant change in the number of osteoclasts. Examination of the growth plate revealed marked disorganization, with an increase in vascularity and matrix. Biomechanical parameters demonstrated increased bone fragility in the hypocalcemic VDR null mice. In the VDR ablated mice in whom normal mineral ion homeostasis had been preserved, none of these measurements was significantly different from those in wild-type littermates raised under identical conditions. Notably, the morphology and width of the growth plate were indistinguishable from those in wild-type controls, demonstrating that a calcium/phosphorus/lactose-enriched diet started at 16 days of age in the VDR null mice permits the development of both normal morphology in the growth cartilage and adjacent metaphysis and normal biomechanical competence of cortical bone. Thus, the principle action of the VDR in skeletal growth, maturation, and remodeling is its role in intestinal calcium absorption. The skeletal consequences of VDR ablation are a result of impaired intestinal calcium absorption and/or the resultant secondary hyperparathyroidism and hypophosphatemia.

Animals↗