Biomedical subjects

Matthias Priemel

Publications and source records attributed to Matthias Priemel.

14 recordsLinked to original sources

PubMed2006

Deleterious tissue reaction to an alkylene bis(dilactoyl)-methacrylate bone adhesive in long-term follow up after screw augmentation in an ovine model.

Biomaterials are designed to support orthopedic surgeons and once implanted they will help the body to heal itself. In this way one of the most attractive substances are biomaterials that allow gluing of bone fragments and implant fixation. Although no bone adhesive is established for practical use in clinical practice yet, there is evidence in vitro and in vivo that a new class of bone adhesives based on alkylene bis(dilactoyl)-methacrylates may meet the requirements to bridge the gap between bench and bedside. The purpose of this experimental study was to investigate the long-term biocompatibility as well as the integration in the remodeling process of a new polymer of this group of substances that was used for both fragment adaptation and implant fixation in a large-scale animal model. In 24 sheep the lateral tibial condyle was osteotomized and refixed by three cortical screws. In 12 of them overdrilling the bone thread of one screw was performed to simulate the poor mechanical properties of osteoporotic bone and the polymer was used in this setting for screw augmentation, furthermore the osteotomy surface was covered with polymer before osteosynthesis to analyze the influence of the material on bone healing. In the other 12 sheep that served as controls osteosynthesis was performed without a polymer. All animals were permitted to walk immediately after surgery under full weight bearing conditions. Six animals of the polymer group and six animals of the control group were analyzed after 6 weeks and 6 months, respectively. Bone healing and implant integration was evaluated by contact X-rays, histology and histomorphometric quantification. After 6 weeks integrity of the healing bone in the polymer group was preserved as compared to the controls, albeit signs of prolonged aseptic inflammation were observed in the polymer group, which is in line with previous reports. In sharp contrast after 6 months, extensive tissue destruction was observed in all animals of the polymer group that was attributed to a massive foreign body reaction at the histological level. These long-term results suggest that (i) short-term observation not always allow valid conclusions regarding the biocompatibility of biomaterials, (ii) that biocompatibility might vary between species, and (iii) that the polymer used in this setting, although previously attributed to be a good candidate for clinical use in patients, does not meet the necessary criteria and tremendously interferes with the physiology of skeletal repair.

Animals↗

PubMed2006

Leptin inhibits bone formation not only in rodents, but also in sheep.

UNLABELLED: This study examines the effect of long-term ICV administration of leptin in ewes. We found that central application significantly decreased osteoblast activity as measured by serum analysis as well as by histomorphometry, resulting in decreased trabecular bone volume. These data provide additional evidence that bone formation and therefore bone remodeling is at least in part centrally controlled. INTRODUCTION: Genetic studies in mice have identified leptin as a potent inhibitor of bone formation acting through the central nervous system and unraveled the central nature of bone mass control and its disorders. Although these studies have radically enhanced our understanding of skeletal physiology because they have established a hypothalamic regulation of bone remodeling through the sympathetic nervous system, controversy remains about the physiological relevance of these observations because leptin's effect on bone after intracerebroventricular (ICV) application has only been shown in mice. To address whether leptin has a role in regulating bone mass beyond rodents, we treated ewes with long-term ICV application of leptin and analyzed the bone phenotype after a treatment period of 3 months. MATERIALS AND METHODS: Three groups of corriedale sheep were compared: (1) control entire (control), (2) ovariectomy (OVX) and ICV application of cerebrospinal fluid (CSF); and (iii) OVX and ICV application of leptin (leptin). Analysis included histomorphometric characterization of iliac crest, spine and femur by histology and biomechanical testing and measurement of bone turnover parameters in serum and urine. RESULTS: Central application of leptin decreased bone formation by 70% and mineralizing surface (MS/BS, 39.4 +/- 3.3% versus 16.1 +/- 2.1%) significantly (p < 0.01). Whereas OVX increased osteoclast indices and urinary cross-lap excretion by two and three times, respectively, serum parameters of osteoblast activity were significantly reduced by ICV application of leptin (p < 0.01). Consequently, ewes treated with leptin were osteopenic (iliac crest BV/TV entire, 22.7 +/- 1.3%; CSF, 18.9 +/- 2.4%; leptin, 12.4 +/- 2.6%), whereas bone torsional failure load reflecting the cortex of the tibia was not yet changed after 3 months of treatment (p < 0.01). CONCLUSIONS: Taken together, these data suggest that leptin controls bone formation after ICV application, leading to reduction of trabecular bone mass in sheep. Most importantly, however, they show that the central regulation of bone formation is not limited to rodents, but is also found in large animals, providing further evidence that bone remodeling in vertebrates is centrally controlled.

Animals↗

PubMed2006

Calcitonin deficiency in mice progressively results in high bone turnover.

UNLABELLED: Although the pharmacological action of calcitonin (CT) as an inhibitor of bone resorption is well established, there is still some controversy regarding its physiological function. Unexpectedly, Calca-deficient mice lacking CT and alpha-calcitonin gene-related peptide (alphaCGRP) were described to have a high bone mass phenotype caused by increased bone formation with normal bone resorption. Here we show that these mice develop a phenotype of high bone turnover with age, suggesting that CT is a physiological inhibitor of bone remodeling. INTRODUCTION: The absence of significant changes in bone mineral density caused by decline or overproduction of CT in humans has raised the question, whether the pharmacological action of CT as an inhibitor of bone resorption is also of physiological relevance. To study the physiological role of mammalian CT, we have analyzed the age-dependent bone phenotype of two mouse models, one lacking CT and alphaCGRP (Calca-/-), the other one lacking only alphaCGRP (alphaCGRP-/-). MATERIALS AND METHODS: Bones from wildtype, Calca-/- -mice and alphaCGRP-/- -mice were analyzed at the ages of 6, 12 and 18 months using undecalcified histology. Differences of bone remodeling were quantified by static and dynamic histomorphometry as well as by measuring the urinary collagen degradation products. To rule out secondary mechanisms underlying the observed phenotype, we determined serum concentrations of relevant hormones using commercially available antibody-based detection kits. RESULTS: Whereas alphaCGRP-/- -mice display an osteopenia at all ages analyzed, the Calca-/- -mice develop a phenotype of high bone turnover with age. Histomorphometric analysis performed at the age of 12 months revealed significant increases of bone formation and bone resorption specifically in the Calca-/- -mice. This severe phenotype that can result in hyperostotic lesions, can not be explained by obvious endocrine abnormalities other than the absence of CT. CONCLUSIONS: In addition to the previously described increase of bone formation in the Calca-deficient mice, we have observed that there is also an increase of bone resorption with age. This suggests that CT has a dual action as an inhibitor of bone remodeling, which may explain why alterations of CT serum levels in humans do not result in major changes of bone mineral density.

Aging↗

PubMed2005

The high mobility group transcription factor Sox8 is a negative regulator of osteoblast differentiation.

Bone remodeling is an important physiologic process that is required to maintain a constant bone mass. This is achieved through a balanced activity of bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we identify the high mobility group transcription factor Sox8 as a physiologic regulator of bone formation. Sox8-deficient mice display a low bone mass phenotype that is caused by a precocious osteoblast differentiation. Accordingly, primary osteoblasts derived from these mice show an accelerated mineralization ex vivo and a premature expression of osteoblast differentiation markers. To confirm the function of Sox8 as a negative regulator of osteoblast differentiation we generated transgenic mice that express Sox8 under the control of an osteoblast-specific Col1a1 promoter fragment. These mice display a severely impaired bone formation that can be explained by a strongly reduced expression of runt-related transcription factor 2, a gene encoding a transcription factor required for osteoblast differentiation. Together, these data demonstrate a novel function of Sox8, whose tightly controlled expression is critical for bone formation.

Animals↗

PubMed2005

Mouse models in skeletal physiology and osteoporosis: experiences and data on 14,839 cases from the Hamburg Mouse Archives.

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, but 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. The input that transgenic animals can offer to our field depends on our means of phenotypic characterization of the mouse skeleton. In fact, full appreciation of the skeletal characteristics of a given mouse model requires the application of standardized protocols for noninvasive imaging, histology, histomorphometry, biomechanics, and individually adapted in vitro and in vivo analysis. Over the past years we have established a mouse archive that consists of 14,839 cases from more than 120 different mouse models that we have phenotypically characterized in Hamburg. Today, this is one of the biggest databases on the mouse skeleton. This review focuses on one aspect of skeletal physiology, namely skeletal aging, and demonstrates that mouse models can be a valuable tool to gain insights in certain facets of skeletal physiology that have been unexplored previously.

Animals↗

PubMed2005

Essential role of RSK2 in c-Fos-dependent osteosarcoma development.

Inactivation of the growth factor-regulated S6 kinase RSK2 causes Coffin-Lowry syndrome in humans, an X-linked mental retardation condition associated with progressive skeletal abnormalities. Here we show that mice lacking RSK2 develop a progressive skeletal disease, osteopenia due to impaired osteoblast function and normal osteoclast differentiation. The phenotype is associated with decreased expression of Phex, an endopeptidase regulating bone mineralization. This defect is probably not mediated by RSK2-dependent phosphorylation of c-Fos on serine 362 in the C-terminus. However, in the absence of RSK2, c-Fos-dependent osteosarcoma formation is impaired. The lack of c-Fos phosphorylation leads to reduced c-Fos protein levels, which are thought to be responsible for decreased proliferation and increased apoptosis of transformed osteoblasts. Therefore, RSK2-dependent stabilization of c-Fos is essential for osteosarcoma formation in mice and may also be important for human osteosarcomas.

Animals↗

PubMed2004

Bone remodeling: new aspects of a key process that controls skeletal maintenance and repair.

Bone remodeling is the concerted interplay of two cellular activities: osteoclastic bone resorption and osteoblastic bone formation. Bone remodeling is the physiologic process that maintains bone mass, skeletal integrity and skeletal function. A molecular understanding of this process is therefore of paramount importance for almost all aspects of skeletal physiology and many facets of bone diseases. Based on the morphological observation of the BMU-"bone multicellular unit" or "bone metabolic unit"-and a wide body of in vitro data, bone remodeling was thought to be controlled locally through functional coupling of resorption and formation and vice versa. However, recent genetic studies have shown that there is no obligatory tight cross-control of bone formation and bone resorption in vivo and that there is also a central axis controlling bone formation, one aspect of bone remodeling. The molecule that inhibits bone formation through a hypothalamic relay is leptin. Following binding to its receptor located on the ventromedial nuclei of the hypothalamus, leptin's action on bone formation is mediated via a neuronal signaling cascade that involves the ss-adrenergic system. The overall goal of this review is to show how the dialogue between clinical medicine and mouse genetics helped to uncover a new concept in skeletal physiology.

Bone Remodeling↗

PubMed2004

Increased bone formation in mice lacking apolipoprotein E.

UNLABELLED: ApoE is a plasma protein that plays a major role in lipoprotein metabolism. Here we describe that ApoE expression is strongly induced on mineralization of primary osteoblast cultures. ApoE-deficient mice display an increased bone formation rate compared with wildtype controls, thereby showing that ApoE has a physiologic function in bone remodeling. INTRODUCTION: Apolipoprotein E (ApoE) is a protein component of lipoproteins and facilitates their clearance from the circulation. This is confirmed by the phenotype of ApoE-deficient mice that have high plasma cholesterol levels and spontaneously develop atherosclerotic lesions. The bone phenotype of these mice has not been analyzed to date, although an association between certain ApoE alleles and BMD has been reported. MATERIALS AND METHODS: Primary osteoblasts were isolated from newborn mouse calvariae and mineralized ex vivo. A genome-wide expression analysis was performed during the course of differentiation using the Affymetrix gene chip system. Bones from ApoE-deficient mice and wildtype controls were analyzed using radiography, micro CT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring urinary collagen degradation products. Lipoprotein uptake assays were performed with (125)I-labeled triglyceride-rich lipoprotein-remnants (TRL-R) using primary osteoblasts from wildtype and ApoE-deficient mice. Serum concentrations of osteocalcin were determined by radioimmunoassay after hydroxyapatite chromatography. RESULTS: ApoE expression is strongly induced on mineralization of primary osteoblast cultures ex vivo. Mice lacking ApoE display a high bone mass phenotype that is caused by an increased bone formation rate, whereas bone resorption is not affected. This phenotype may be explained by a decreased uptake of triglyceride-rich lipoproteins by osteoblasts, resulting in elevated levels of undercarboxylated osteocalcin in the serum of ApoE-deficient mice. CONCLUSION: The specific induction of ApoE gene expression during osteoblast differentiation along with the increased bone formation rate observed in ApoE-deficient mice shows that ApoE has a physiologic role as a regulator of osteoblast function.

Alleles↗

PubMed2004

Decreased bone formation and osteopenia in mice lacking alpha-calcitonin gene-related peptide.

UNLABELLED: We recently described an unexpected high bone mass phenotype in mice lacking the Calca gene that encodes CT and alphaCGRP. Here we show that mice specifically lacking alphaCGRP expression display an osteopenia caused by a decreased bone formation. These results show that alphaCGRP is a physiological activator of bone formation and that the high bone mass phenotype of the Calca-deficient mice is caused by the absence of CT. INTRODUCTION: Calcitonin (CT) and alpha-calcitonin gene-related peptide (alphaCGRP) are two polypeptides without completely defined physiologic functions that are both derived from the Calca gene by alternative splicing. We have recently described an unexpected high bone mass phenotype in mice carrying a targeted deletion of the Calca gene. To uncover whether this phenotype is caused by the absence of CT or by the absence of alphaCGRP, we analyzed a mouse model, where the production of alphaCGRP is selectively abolished. MATERIALS AND METHODS: Bones from Calca(-/-) mice, alphaCGRP(-/-) mice, and their corresponding wildtype controls were analyzed using radiography, muCT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring the urinary collagen degradation products. CT expression was determined using radioimmunoassay and RT-PCR. Immunohistochemistry was performed using an anti-CGRP antibody on decalcified bone sections. RESULTS: Unlike the Calca-deficient mice, the alphaCGRP-deficient mice do not display a high bone mass phenotype. In contrast, they develop an osteopenia that is caused by a reduced bone formation rate. Serum levels and thyroid expression of CT are not elevated in alphaCGRP-deficient mice. While CGRP expression is detectable in neuronal cell close to trabecular bone structures, the components of the CGRP receptor are expressed in differentiated osteoblast cultures. CONCLUSION: The discrepancy between the bone phenotypes of Calca(-/-) mice and alphaCGRP(-/-) mice show that the high bone mass phenotype of the Calca(-/-) mice is caused by the absence of CT. The osteopenia observed in the alphaCGRP(-/-) mice that have normal levels of CT further show that alphaCGRP is a physiologic activator of bone formation.

Alternative Splicing↗

PubMed2004

Determinants and heterogeneity of mechanical competence throughout the thoracolumbar spine of elderly women and men.

Vertebral fractures represent the hallmark of osteoporosis. Here, we test the hypotheses that (sub)cortical bone strength and density predict failure better than trabecular core strength and density, and that elderly women display lower failure stress of thoracic vertebrae than men. We examined the vertebral bodies T3 to L5 in 39 spines from elderly donors (23 women; 16 men; age 79 +/- 11 years). Peripheral quantitative computed tomography was used to measure total, trabecular, and (sub)cortical bone density. Mechanical tests were performed in functional spinal units, planoparallel sections of vertebrae, trabecular cores, and (sub)cortical ring specimens. The failure stress decreased with descending vertebral level. Failure stress was highest for the (sub)cortical rings and planoparallel sections and lowest for the trabecular core. The failure stress did not differ significantly between men and women. Mechanical strength of the functional unit was more strongly correlated with the strength of the (sub)cortical ring (r = 0.78) than with that of the trabecular core (r = 0.62). However, total density was more highly correlated with mechanical strength of the same and remote vertebrae (r = 0.63) than trabecular (r = 0.50) or (sub)cortical density (r = 0.36), respectively. The results show that vertebral strength is similar in elderly women and men. Strength of (sub)cortical bone provides significantly better prediction of strength of functional spinal units than that of the trabecular core. However, total density predicts functional segment failure stress with higher accuracy than (sub)cortical or trabecular density and is thus recommended for predicting fracture strength clinically.

Aged↗

PubMed2004

Clinical relevance of calcaneal bone cysts: a study of 50 cysts in 47 patients.

The clinical relevance and nature of calcaneal cysts is controversial. The risk of pathologic fracture is undefined and diagnostic criteria to differentiate between cysts in patients who can be treated nonoperatively and patients who require surgical intervention are not available. To address these questions, 50 calcaneal bone cysts in 47 patients were evaluated. The majority of cysts (40 of 50) were asymptomatic and were treated nonoperatively. Cysts reaching a critical size, defined as 100% intracalcaneal cross section in the coronary plane and at least 30% in the sagittal plane, are at risk for becoming symptomatic and at risk for fracture. Fracture is a significant complication and occurred in four of 47 patients, three of whom were treated by open reduction internal fixation and bone grafting. In addition, six patients with symptomatic critical size cysts without apparent fracture were treated by curettage and subsequent autogenous bone grafting or calcium-phosphate cement filling, and there were no recurrences. We report one of the largest series of cysts in the calcaneus. The results suggest that calcaneal cysts are clinically relevant because of the potential risk of fracture and that size is a significant factor in terms of the treatment of the cyst.

Adolescent↗

PubMed2003

Aneurysmal bone cysts of the sacrum. Clinical report and review of the literature.

BACKGROUND: Aneurysmal bone cysts, first described by Jaffe and Lichtenstein in 1942, are benign lesions that may easily be mistaken for a malignant tumor both radiographically and pathologically. These diagnostic problems are due to their rapid growth, extensive destruction of bone, wide extraosseous tumor masses, and marked cellular exuberance. The differential diagnosis of aneurysmal bone cysts including giant cell tumor, calcified solitary bone cysts, low-grade osteosarcoma, and teleangiectatic osteosarcoma becomes even more complicated when the lesion arises at sites other than the long bones and presents with extensive extraosseous, soft-tissue tumor masses. The latter cases--especially when they occur as sacral or presacral tumors--present challenges with respect to successful treatment, which should combine surgical removal of the entire lesion following oncological criteria to prevent recurrences and osteosynthesis to guarantee the biomechanical stability of the spinal-pelvic junction. Here we report on the clinical case of a female patient with an aneurysmal bone cyst of the sacrum and extensive extraosseous tumor masses. The report includes the diagnostic challenges, the surgical options of sacral and/or presacral tumors, the histopathological findings, and long-term clinical and radiographic surveillance. METHODS: The patient was treated by a combination of preoperative adjuvant selective arterial embolization, radical surgical excision through an anterior approach followed by subsequent osteosynthesis and stabilization through a posterior approach. RESULTS: Clinical and radiographic follow-up for 2 years was uneventful, and the patient is still free of recurrence or any complaints. CONCLUSION: The current report documents the diagnostic and surgical challenge of a gigantic aneurysmal bone cyst of the sacrum and its successful management.

Adolescent↗

PubMed2003

Precision and accuracy of peripheral quantitative computed tomography (pQCT) in the mouse skeleton compared with histology and microcomputed tomography (microCT).

UNLABELLED: pQCT was evaluated for accuracy of phenotypic characterization of mouse bone in vivo. Bones (tibia, femur, spine) of 27 animals were measured ex vivo with pQCT, microCT, and histomorphometry and of 23 mice in vivo (pQCT). pQCT yielded satisfactory in vivo precision and accuracy in skeletal characterization. INTRODUCTION: Important aspects of modern skeletal research depend on the phenotypic characterization of genetically manipulated mice, with some approaches requiring in vivo measurement. Peripheral quantitative computed tomography (pQCT) is applicable in vivo and provides opportunities to determine a large variety of bone parameters. Here we test the ex vivo and in vivo reproducibility of pQCT, and its accuracy in comparison with histomorphometry and microcomputed tomography (microCT). MATERIALS AND METHODS: We examined the tibia, femur, and lumbar spine of 27 mice ex vivo with high-resolution pQCT, using two mouse models (wild-type and ob/ob) with known differences in bone density. Measurements were repeated three times at different days in nine animals. In a second experiment, 23 animals (10 wild-type and 13 bGH transgenic mice) were repeatedly measured in vivo at 12 and 13 weeks of age, respectively. RESULTS: Among metaphyseal sites, the ex vivo precision was highest at the distal femur (RMS CV < 1% for density and < 2% for area). The correlation between density (pQCT) and bone volume fraction (histomorphometry) was r2 = 0.79 (tibia, femur, and spine), and that with microCT was r2 = 0.94 (femur). At the diaphysis, the precision was highest at the femur (< 2% for total and cortical area), and the correlation with microCT was r2 > 0.77. The in vivo precision for bone density (distal femur) was 2.3-5.1%, and that for absolute and relative cortical area (tibia) was 3.1% and 2.2%. CONCLUSIONS: The results show that pQCT can yield satisfactory precision and accuracy in skeletal characterization of mouse bones, if properly applied. The potential advantage of pQCT is that it provides a large set of parameters on bone properties and that it can be used in vivo, extending the available methodological repertoire for genetic studies.

Animals↗

PubMed2002

Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene.

Calcitonin (CT) is a known inhibitor of bone resorption. Calcitonin gene-related peptide-alpha (CGRPalpha), produced by alternative RNA processing of the CT/CGRP gene, has no clearly defined role in bone. To better understand the physiologic role of the CT/CGRP gene we created a mouse in which the coding sequences for both CT and CGRPalpha were deleted by homologous recombination. The CT/CGRP(-/-) knockout (KO) mice procreated normally, there were no identifiable developmental defects at birth, and they had normal baseline calcium-related chemistry values. However, KO animals were more responsive to exogenous human parathyroid hormone as evidenced by a greater increase of the serum calcium concentration and urine deoxypyridinoline crosslinks, an effect reversed by CT and mediated by a greater increase in bone resorption than in controls. Surprisingly, KO mice have significantly greater trabecular bone volume and a 1.5- to 2-fold increase in bone formation at 1 and 3 months of age. This effect appears to be mediated by increased bone formation. In addition, KO mice maintain bone mass following ovariectomy, whereas wild-type mice lose approximately one-third of their bone mass over 2 months. These findings argue for dual roles for CT/CGRP gene products: prevention of bone resorption in hypercalcemic states and a regulatory role in bone formation.

Alternative Splicing↗