Snail1 controls bone mass by regulating Runx2 and VDR expression during osteoblast differentiation

Bone undergoes continuous remodelling throughout adult life, and the equilibrium between bone formation by osteoblasts and bone resorption by osteoclasts defines the final bone mass. Here we show that Snail1 regulates this balance by controlling osteoblast differentiation. Snail1 is necessary for the early steps of osteoblast development, and it must be downregulated for their final differentiation. At the molecular level, Snail1 controls bone mass by repressing the transcription of both the osteoblast differentiation factor Runx2 and the vitamin D receptor (VDR) genes in osteoblasts. Sustained activation of Snail1 in transgenic mice provokes deficient osteoblast differentiation, which, together with the loss of vitamin D signalling in the bone, also impairs osteoclastogenesis. Indeed, the mineralisation of the bone matrix is severely affected, leading to hypocalcemia-independent osteomalacia. Our data show that the impact of Snail1 activity on the osteoblast population regulates the course of bone cells differentiation and ensures normal bone remodelling

New Suggestions for the Mechanical Control of Bone Remodeling

Bone is constantly renewed over our lifetime through the process of bone (re)modeling. This process is important for bone to allow it to adapt to its mechanical environment and to repair damage from everyday life. Adaptation is thought to occur through the mechanosensitive response controlling the bone-forming and -resorbing cells. This report shows a way to extract quantitative information about the way remodeling is controlled using computer simulations. Bone resorption and deposition are described as two separate stochastic processes, during which a discrete bone packet is removed or deposited from the bone surface. The responses of the bone-forming and -resorbing cells to local mechanical stimuli are described by phenomenological remodeling rules. Our strategy was to test different remodeling rules and to evaluate the time evolution of the trabecular architecture in comparison to what is known from μ-CT measurements of real bone. In particular, we tested the reaction of virtual bone to standard therapeutic strategies for the prevention of bone deterioration, i.e., physical activity and medications to reduce bone resorption. Insensitivity of the bone volume fraction to reductions in bone resorption was observed in the simulations only for a remodeling rule including an activation barrier for the mechanical stimulus above which bone deposition is switched on. This is in disagreement with the commonly used rules having a so-called lazy zone

Histomorphometric evaluation of bone healing in rabbit fibular osteotomy model without fixation

<p>Abstract</p> <p>Background</p> <p>Animal models of fracture consolidation are fundamental for the understanding of the biological process of bone repair in humans, but histological studies are rare and provide only qualitative results. The objective of this article is to present the histomorphometric study of the bone healing process using an experimental model of osteotomy in rabbit fibula without interference of synthesis material.</p> <p>Methods</p> <p>Fifteen rabbits were submitted to fibular osteotomy without any fixation device. Groups of five animals were submitted to pharmacological euthanasia during a period of one (group A), two (group B) and four weeks (group C) after osteotomy. Histomorphometric evaluation was performed in the histological sections.</p> <p>Results</p> <p>During week one there was intense cellularity (67/field), a large amount of woven bone (75.7%) and a small amount of lamellar bone (7.65%). At two weeks there was a decrease in woven bone (41.59%) and an increase in lamellar bone (15.16%). At four weeks there was a decrease of cellularity (19.17/field) and lamellar bone (55.56%) exceeded the quantity of woven bone (31.68%).</p> <p>Conclusion</p> <p>Histomorphometric (quantitative) evaluation of the present study was shown to be compatible with bone healing achieved in qualitative experimental models that have been commended in the literature.</p

Severity of hearing loss after platinum chemotherapy in childhood cancer survivors.

BACKGROUND Hearing loss is a potential side effect from childhood cancer treatment. We described the severity of hearing loss assessed by audiometry in a representative national cohort of childhood cancer survivors (CCS) and identified clinical risk factors. PROCEDURE We included all CCS from the Swiss Childhood Cancer Registry who were diagnosed ≤18 age and treated with platinum-based chemotherapy between 1990 and 2014. We extracted audiograms, treatment-related information, and demographic data from medical records. Two reviewers independently assessed the severity of hearing loss at latest follow-up using the Münster Ototoxicity Scale. We used ordered logistic regression to identify clinical risk factors for severity of hearing loss. RESULTS We analyzed data from 270 CCS. Median time from cancer diagnosis to last audiogram was 5 years (interquartile range 2.5-8.1 years). We found 53 (20%) CCS with mild, 78 (29%) with moderate, and 75 (28%) with severe hearing loss. Higher severity grades were associated with (a) younger age at cancer diagnosis (odds ratio [OR] 5.4, 95% confidence interval [CI]: 2.5-12.0 for 450 mg/m2 ); (d) concomitant cranial radiation therapy (CRT) (OR 4.4, 95% CI: 2.5-7.8); and (e) hematopoietic stem cell transplantation (HSCT) (OR 2.7, 95% CI: 1.0-7.2). CONCLUSION Three of four CCS treated with platinum-based chemotherapy experienced some degree of hearing loss. We recommend closely monitoring patient's hearing function if treated at a young age with high cumulative cisplatin doses, and concomitant CRT as part of long-term care

Salvianolic Acid B Prevents Bone Loss in Prednisone-Treated Rats through Stimulation of Osteogenesis and Bone Marrow Angiogenesis

Glucocorticoid (GC) induced osteoporosis (GIO) is caused by the long-term use of GC for treatment of autoimmune and inflammatory diseases. The GC related disruption of bone marrow microcirculation and increased adipogenesis contribute to GIO development. However, neither currently available anti-osteoporosis agent is completely addressed to microcirculation and bone marrow adipogenesis. Salvianolic acid B (Sal B) is a polyphenolic compound from a Chinese herbal medicine, Salvia miltiorrhiza Bunge. The aim of this study was to determine the effects of Sal B on osteoblast bone formation, angiogenesis and adipogenesis-associated GIO by performing marrow adipogenesis and microcirculation dilation and bone histomorphometry analyses. (1) In vivo study: Bone loss in GC treated rats was confirmed by significantly decreased BMD, bone strength, cancellous bone mass and architecture, osteoblast distribution, bone formation, marrow microvessel density and diameter along with down-regulation of marrow BMPs expression and increased adipogenesis. Daily treatment with Sal B (40 mg/kg/d) for 12 weeks in GC male rats prevented GC-induced cancellous bone loss and increased adipogenesis while increasing cancellous bone formation rate with improved local microcirculation by capillary dilation. Treatment with Sal B at a higher dose (80 mg/kg/d) not only prevented GC-induced osteopenia, but also increased cancellous bone mass and thickness, associated with increase of marrow BMPs expression, inhibited adipogenesis and further increased microvessel diameters. (2) In vitro study: In concentration from 10−6 mol/L to 10−7 mol/L, Sal B stimulated bone marrow stromal cell (MSC) differentiation to osteoblast and increased osteoblast activities, decreased GC associated adipogenic differentiation by down-regulation of PPARγ mRNA expression, increased Runx2 mRNA expression without osteoblast inducement, and, furthermore, Sal B decreased Dickkopf-1 and increased β-catenin mRNA expression with or without adipocyte inducement in MSC. We conclude that Sal B prevented bone loss in GC-treated rats through stimulation of osteogenesis, bone marrow angiogenesis and inhibition of adipogenesis

The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation

Background: Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype. Methodology/Principal Findings: We found that Per2Brdm1 mutant mice as well as mice lacking Cry2-/- displayed significantly increased bone volume at 12 weeks of age, when bone turnover is high. Per2Brdm1 mutant mice showed alterations in parameters specific for osteoblasts whereas mice lacking Cry2-/- displayed changes in osteoclast specific parameters. Interestingly, inactivation of both Per2 and Cry2 genes leads to normal bone volume as observed in wild type animals. Importantly, osteoclast parameters affected due to the lack of Cry2, remained at the level seen in the Cry2-/- mutants despite the simultaneous inactivation of Per2. Conclusions/Significance: This indicates that Cry2 and Per2 affect distinct pathways in the regulation of bone volume with Cry2 influencing mostly the osteoclastic cellular component of bone and Per2 acting on osteoblast parameters

Malignant PEComa: a case report with emphasis on clinical and morphological criteria

<p>Abstract</p> <p>Background</p> <p>Malignant perivascular epitheliod cell tumor (PEComa) is a very rare entity composed of distinctive perivascular epitheliod cells with variable immunoreactivity for melanocytic and muscle markers. At present this neoplasm does not have a known normal cellular counterpart and the natural history is often unpredictable. Up to now, few cases of PEComa have been described and treatment modalities are still controversial, particularly in advanced conditions.</p> <p>Case presentation</p> <p>We handled the case of a 42-year-old man with unresectable PEComa of the abdomen. A 7 cm hepatic hypodense lesion between segment V and VIII of the liver and diffuse intraperitoneal nodules of 0,3-3,5 cm along the right subcapsular hepatic region, were documented by a CT scan. Radiological images showed abnormal lymph nodes of the right internal mammary chain and anterior mediastinum. The patient underwent an explorative laparotomy for uncontrolled intrabdominal hemorrhage without a well-defined preoperative tumor diagnosis. At surgery, multiple lobulated nodules containing hemorrhagic fluid on the liver surface, peritoneum and omentum were confirmed. The procedure had a palliative intent and consisted of hemostasis, hematomas evacuation and omentectomy. The diagnosis of PEComa was made after surgery on the basis of morphological and immunohystochemical criteria. Radiological and intra operative findings suggest that the mass has an hepatic origin with diffuse involvement of hepatic capsule and suspensory ligaments. The patient received medical support care with blood and plasma transfusions. In our experience, PEComa was clinically malignant, leading to a fatal outcome 25 days after hospital admission of patient.</p> <p>Conclusions</p> <p>Here we report and discuss the peculiar clinical, radiological and morphological presentation of unresectable PEComa. Although in the majority of the reported series, PEComas show a more better prognosis, our case presents with a particular aggressive biological behaviour. The importance of a correct preoperative diagnosis, the need for more effective targeted therapies based on tumor molecular knowledge and evidence-based clinical studies are emphasized together with a revision of the concerning scientific literature.</p

Cthrc1 Is a Positive Regulator of Osteoblastic Bone Formation

Bone mass is maintained by continuous remodeling through repeated cycles of bone resorption by osteoclasts and bone formation by osteoblasts. This remodeling process is regulated by many systemic and local factors.We identified collagen triple helix repeat containing-1 (Cthrc1) as a downstream target of bone morphogenetic protein-2 (BMP2) in osteochondroprogenitor-like cells by PCR-based suppression subtractive hybridization followed by differential hybridization, and found that Cthrc1 was expressed in bone tissues in vivo. To investigate the role of Cthrc1 in bone, we generated Cthrc1-null mice and transgenic mice which overexpress Cthrc1 in osteoblasts (Cthrc1 transgenic mice). Microcomputed tomography (micro-CT) and bone histomorphometry analyses showed that Cthrc1-null mice displayed low bone mass as a result of decreased osteoblastic bone formation, whereas Cthrc1 transgenic mice displayed high bone mass by increase in osteoblastic bone formation. Osteoblast number was decreased in Cthrc1-null mice, and increased in Cthrc1 transgenic mice, respectively, while osteoclast number had no change in both mutant mice. In vitro, colony-forming unit (CFU) assays in bone marrow cells harvested from Cthrc1-null mice or Cthrc1 transgenic mice revealed that Cthrc1 stimulated differentiation and mineralization of osteoprogenitor cells. Expression levels of osteoblast specific genes, ALP, Col1a1, and Osteocalcin, in primary osteoblasts were decreased in Cthrc1-null mice and increased in Cthrc1 transgenic mice, respectively. Furthermore, BrdU incorporation assays showed that Cthrc1 accelerated osteoblast proliferation in vitro and in vivo. In addition, overexpression of Cthrc1 in the transgenic mice attenuated ovariectomy-induced bone loss.Our results indicate that Cthrc1 increases bone mass as a positive regulator of osteoblastic bone formation and offers an anabolic approach for the treatment of osteoporosis

Generation and Characterization of Mouse Models for Skeletal Disease

Our laboratories have used genetically engineered mouse models (GEMMs) to assess genetic contributions to skeletal diseases such as osteoporosis and osteoarthritis. Studies on the genetic contributions to OA are often done by assessing how GEMMs respond to surgical methods that induce symptoms modeling OA. Here, we will describe protocols outlining the induction of experimental OA in mice as well as detailed descriptions of methods for analyzing skeletal phenotypes using micro-computerized tomography and skeletal histomorphometry

The influence of long-term treadmill exercise on bone mass and articular cartilage in ovariectomized rats

<p>Abstract</p> <p>Background</p> <p>Loss of bone quality and deterioration of articular cartilage are commonly seen after menopause. While exercise may protect against tissue degeneration, a clear link has yet to be established. The aim of the present study is to investigate the influence of long-term treadmill exercise on changes in bone mass and articular cartilage in ovariectomized rats.</p> <p>Methods</p> <p>Sixty female Sprague-Dawley rats were randomly assigned to 4 groups: ovariectomized (OVX), ovariectomized plus treadmill exercise (OVX-RUN), treadmill exercise alone (RUN), and control (CON) groups. After 36 weeks, the following variables were compared among the 4 groups. Bone mass was evaluated by trabecular bone volume and bone mineral density (BMD). Articular cartilage in the knee joints was evaluated by histology analysis and a modified Mankin score.</p> <p>Results</p> <p>Rats in the ovariectomized groups (OVX and OVX-RUN) had significantly lower BMD and bone mass than the non-ovariectomized rats (CON and RUN), indicating that exercise did little to preserve bone mass. However, the sedentary OVX group had a significantly worse modified Mankin score (7.7 ± 1.4) than the OVX-RUN group (4.8 ± 1.0), whose scores did not differ significantly from the other 2 non-operated groups. The articular cartilage in the sedentary OVX rats was relatively thinner, hypocellular, and had more clefts than in the other 3 groups.</p> <p>Conclusion</p> <p>This study suggests that long-term exercise protects articular cartilage in OVX rats but does not retard the loss of bone mass seen in after menopause.</p