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Biomedical subjects

M Amling

Publications and source records attributed to M Amling.

At least 19 recordsLinked to original sources
PubMed2007

High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K.

INTRODUCTION: Pycnodysostosis is typically associated with short stature, multiple fractures without adequate trauma and high bone density on x-ray. The increased bone density is due to a genetic defect of cathepsin K, leading to dysfunctional osteoclastic bone resorption and bone remodeling. We wanted to know how this defect influences the trabecular and cortical volumetric bone mineral density of long bones as measured quantitatively by pQCT. METHODS: Three siblings of a consanguineous family were admitted to our hospital because of multiple fractures. Pycnodysostosis was diagnosed based on the clinical presentation with the characteristic dense appearance of their bones on x-ray. The distal and proximal radius of the patients and of control subjects was scanned using a Stratec XCT-2000 pQCT scanner and data were processed using the software provided by the manufacturer. Genomic DNA was extracted from blood samples of all three patients and their parents. The coding exons of the cathepsin K gene (CTSK) were amplified and sequenced. RESULTS: The patients displayed the typical features of pycnodysostosis: Short stature, delay of closure of the fontanelles, hypoplasia of the maxilla, spondylolysis of the lumbar spine, stubby hands and feet and a history of multiple fractures. Volumetric bone density was much higher in pycnodysostotic bone than in the control bones 686 +/- 28 mg/cm(3) in patients vs. 290 +/- 6 mg/cm(3) in controls; p = 0.001), especially in the trabecular compartment (733 +/- 26 mg/cm(3) in patients vs. 195 +/- 8 mg/cm(3) in controls; p < 0.001), but also in the cortical bone (1108 +/- 22 in patients vs. 1020 +/- 17 in controls; p < 0.01). In contrast to this finding, the patients displayed an elevation of alkaline phosphatase in the serum and free deoxypyridinoline-crosslinks (DPD) in the urine, suggesting osteomalacia. Sequencing of the cathepsin K gene revealed homozygosity for a novel missense mutation in all three patients predicting the amino acid exchange from arginine to tryptophan at position 46 (R46W). CONCLUSION: We present here for the first time quantitative data on the mineral density of bones of pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. The elevated bone mineral density in the cortex and the changes in the serum markers suggest an effect of cathepsin K not only on bone volume, but also on bone mineralization. This might in part explain the increased susceptibility to fractures of patients with pycnodysostosis.

Absorptiometry, Photon↗
PubMed2007

[The calcaneus as the site of manifestation for osteoporosis-associated fractures: age- and sex-specific changes in calcaneal morphology correlate with the incidence and severity of intra-articular calcaneal fractures].

BACKGROUND: While it is recognized that trauma energy at the time of injury is an important factor in the pathogenesis and severity of calcaneal fractures, the possible role of changes in calcaneal microarchitecture remains largely undefined. The purpose of this study was to determine whether the calcaneal bone structure changes with age and to address if local bone mass is of clinical relevance in respect to the occurrence and complexity of calcaneal fractures. MATERIAL AND METHODS: The radiographic and clinical data of 182 patients with intra-articular calcaneal fractures were analyzed to provide correlative clinical evidence for a relation between local bone mass and fractures of the calcaneus. To measure bone mass, 60 calcanei were harvested from 30 age- and gender-matched patients at autopsy. RESULTS: The average age at the time of fracture was higher in females (46.0+/-18.3 years) than in males (39.9+/-13.9 years). Furthermore, the relative frequency of fractures during aging shifted from males to females and the frequency of compound fractures was higher in females (65%) than in males (48%). The calcaneal bone mass was significantly reduced by 19% in older females (female symbol 20-40 years: 292 mg/cm(3); female symbol 61-80 years: 237 mg/cm(3); p<0.05). CONCLUSION: The calcaneus displayed age- and gender-related changes in its microarchitecture that are known to reduce the biomechanical stability of trabecular bone. These results suggest that bone mass and structure are risk factors in respect to the occurrence and severity of calcaneal fractures.

Adult↗
PubMed2007

[Subdental synchondrosis. Computed tomographic and histologic investigation on morphological aspects of fracture at the base of the dens in 36 human axis specimens].

BACKGROUND: During development of the axis, four different ossification centers are formed. The two cranial ossification centers are demarcated from the ossification center of the vertebral corpus by a subdental synchondrosis. During further development the subdental synchondrosis--which is thought to close spontaneously--might not close completely, which leads to the necessity for differentiating synchondrotic remnants from a fracture at the base of the dens (type II according to Anderson and D'Alonzo). RESULTS: To characterize the architecture of the axis with particular attention to the subdental synchondrosis, the axis was harvested from 36 age- and gender-matched patients covering the human aging process from adolescence to senescence. In all specimens bone mineral density (BMD) was measured by peripheral quantitative computed tomography (pQCT). Morphological analysis after undecalcified processing of all specimens revealed a persistency of the subdental synchondrosis in 87% of all patients. Histological characterization of the subdental synchondrosis showed a cartilaginous structure interspersed with focal mineralization. Furthermore, static histomorphometric analysis revealed that trabecular bone volume and cortical thickness were significantly reduced within the base of the axis as compared to the dens and the corpus, respectively. CONCLUSION: Taken together, these results provide evidence that the base of the axis is a structurally distinct region. Besides well-recognized biomechanical aspects, these results suggest that the structure of the base of the axis might contribute to the occurrence of fractures of the axis and offer an additional explanation for the observation of nonunion after type II dens fractures.

Adolescent↗
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

[Mechanical failure of porous hydroxyapatite ceramics 7.5 years after implantation in the proximal tibial].

The treatment of osseous defects is widely established in the elderly. The number of positive reports on the successful application of bovine as well as coralline hydroxyapatite ceramics has continuously increased during the last few years. In trauma surgery hydroxyapatite ceramics are most commonly applied in metaphyseal defects evoked by traumatic fractures of the long bones. The bovine and coralline materials applied are biocompatible and exhibit an interconnecting porous system. Good osteoconductive properties of such materials have repeatedly been demonstrated. Due to possible harmful effects caused by abrasion of the material, intra-articular application should be strictly avoided. Biological degradation of the materials does not occur even during long-term follow-up. The application of hydroxyapatite ceramics was introduced at our institution in 1992. Since then, no adverse events have been observed and only a few relevant complications were described in the literature. We report on a patient revealing a mechanical failure of a bovine hydroxyapatite (Endobon) 7.5 years after implantation into a metaphyseal defect of the proximal tibia caused by a traumatic fracture.

Athletic Injuries↗
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↗
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

Biologically and chemically optimized composites of carbonated apatite and polyglycolide as bone substitution materials.

We report on the development and characterization of a new composite material consisting of amorphous carbonated apatite, Ca(5)(PO(4), CO(3))(3)(OH), and microstructured poly(hydroxyacetic acid), polyglycolide (PGA). This material is able to keep the pH of a surrounding solution within the physiological range (7.2-7.6). This was achieved by chemical fine-tuning of the counterplay between the acidic degradation of the polyester and the basic dissolution of calcium phosphate. Microporous samples with pore sizes of <1 microm and compact samples were prepared. The biological behavior was assayed in vitro by long-term osteoblast culture. Morphological and biochemical analyses of cell differentiation revealed excellent biocompatibility, leading to cell attachment, collagen and osteocalcin expression, and mineral deposition. This material could be of use as a biodegradable bone substitution material and as a scaffold for tissue engineering.

Animals↗
PubMed2001

[Leptin: factor in the central nervous system regulation of bone mass. Development of a new understanding of bone remodeling, skeletal reconstruction, skeletal preservation and skeletal repair].

Bone remodeling is the physiologic process used by vertebrates to maintain a constant bone mass between the end of puberty and gonadal failure. Besides the well-characterized and critical local regulation of bone remodeling, recent genetic studies have shown that there is a central control of bone formation, one aspect of bone remodeling. This central regulation involves leptin, an adipocyte-secreted hormone that controls body weight, reproduction, and bone remodeling following binding to its receptor located on the hypothalamic nuclei. This genetic result in rodents is in line with clinical observations in humans and offers a whole new direction for research in bone physiology.

Adolescent↗
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

A neuro (endo)crine regulation of bone remodeling.

Bone remodeling is the normal physiologic process that is used by vertebrates to maintain a constant bone mass during the period bracketed by the end of puberty and the onset of gonadal failure in later life. Besides the well-characterized and critical process of local regulation of bone remodeling, achieved by autocrine and paracrine mechanisms, recent genetic studies have shown that there is a central control of bone formation, mediated by a neuroendocrine mechanism. This central regulation involves leptin, an adipocyte-secreted hormone that controls body weight, reproduction and bone remodeling, and which binds to and exerts its effect through the cells of the hypothalamic nuclei in the brain. This genetic result in mice is in line with clinical observations in humans and generates a whole new direction of research in bone physiology. BioEssays 22:970-975, 2000.

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

Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis.

Members of the AP-1 family of transcription factors participate in the regulation of bone cell proliferation and differentiation. We report here a potent AP-1-related regulator of osteoblast function: DeltaFosB, a naturally occurring truncated form of FosB that arises from alternative splicing of the fosB transcript and is expressed in osteoblasts. Overexpression of DeltaFosB in transgenic mice leads to increased bone formation throughout the skeleton and a continuous post-developmental increase in bone mass, leading to osteosclerosis. In contrast, DeltaFosB inhibits adipogenesis both in vivo and in vitro, and downregulates the expression of early markers of adipocyte differentiation. Because osteoblasts and adipocytes are thought to share a common precursor, it is concluded that DeltaFosB transcriptionally regulates osteoblastogenesis, possibly at the expense of adipogenesis.

Adipocytes↗