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Mortality of patients with end-stage renal disease tremendously exceeds that of the general population due to excess cardiovascular morbidity. Large middle-sized molecules (LMM) including pro-inflammatory cytokines are major drivers of uremic cardiovascular toxicity and cannot be removed sufficiently by conventional high-flux (HFL) hemodialysis. We tested the ability of plasma from 19 hemodialysis patients participating in a trial comparing HFL with high cut-off (HCO) membranes facilitating removal of LMM to induce calcification in mesenchymal stromal cells (MSC) functioning as vascular progenitors. HCO dialysis favorably changed plasma composition resulting in reduced pro-calcific activity. LMM were removed more effectively by HCO dialysis including FGF23, a typical LMM we found to promote osteoblastic differentiation of MSC. Protein-bound uremic retention solutes with known cardiovascular toxicity but not LMM inhibited proliferation of MSC without direct toxicity in screening experiments. We could not attribute the effect of HCO dialysis on MSC calcification to distinct mediators. However, we found evidence of sustained reduced inflammation that might parallel other anti-calcifying mechanisms such as altered generation of extracellular vesicles. Our findings imply protection of MSC from dysfunctional differentiation by novel dialysis techniques targeted at removal of LMM. HCO dialysis might preserve their physiologic role in vascular regeneration and improve outcomes in dialysis patients.

The aim of this study was to investigate the healing of human extraction sockets filled with β-tricalcium phosphate and type I collagen (β-TCP/Clg) cones with or without a barrier membrane. Twenty patients were divided in two groups: (A) β-TCP/Clg non-membrane and (B) β-TCP/Clg + barrier membrane. Clinical examination and biopsies from the grafted sites were collected 9 months later. Bone samples were analyzed using histomorphometry and immunohistochemistry. The horizontal dimension of the alveolar ridge was significantly reduced 9 months after socket preservation in the non-membrane group. There was bone formation with no significant differences between the two groups in the areas occupied by new bone (A = 42.4%; B = 45.3%), marrow (A = 42.7%; B = 35.7%), or residual graft (A = 9.7%; B = 12.5%). Immunohistochemistry revealed osteonectin expression in both groups. Both groups demonstrated sufficient amounts of vital bone and socket morphology to support dental implant placement after the 9-month healing period. A future trial to evaluate the alveolar outcomes at an earlier 6-month time point rather than the 9 months used in this study would be of interest.

Background Our study aim was to compare allogeneic cancellous bone (ACB) and synthetic or highly-processed xenogeneic bone substitutes (SBS) in the treatment of skeletal defects in orthopedic surgery. Methods 232 patients treated for bony lesions with ACB ( n  = 116) or SBS ( n  = 116) within a 10-year time period were included in this case–control study. Furthermore, both materials were seeded with human osteoblasts (hOB, n  = 10) and analyzed by histology, for viability (AlamarBlue®) and protein expression activity (Luminex®). Results The complication rate was 14.2 %, proportion of defects without bony healing 3.6 %; neither outcome parameter differed comparing the intervention groups. Failed consolidation correlated with an increase in complications ( p  < 0.03). The rate of complications was further highly significant in association with the location of use ( p  < 0.001), but did not depend on age, ASA risk classification, BMI, smoking behavior or type of insurance. However, those factors did significantly influence the bony healing rate ( p  < 0.02). Complication and consolidation rates were independent of gender and the filling substances employed within the different locations. Histological examination revealed similar bone structures, whereas cell remnants were apparent only in the allografts. Both materials were biocompatible in-vitro, and seeded with human osteoblasts. The cells remained vital over the 3-week culture period and produced microscopically typical bone matrix. We observed initially increased expression of osteocalcin, osteopontin, and osteoprotegerin as well as leptin and adiponectin secretion declining after 1 week, especially in the ACB group. Conclusion Although both investigated materials appeared to be similarly suitable for the treatment of skeletal lesions in-vivo and in-vitro, outcome was decisively influenced by other factors such as the site of use or epidemiological parameters.

BackgroundSkeletal-related events (SREs), common sequelae of metastatic cancer, are reduced by bisphosphonates. In this study, it was postulated that radiopharmaceuticals, added to bisphosphonates, could further decrease the incidence of SREs.MethodsNRG Oncology RTOG 0517 randomized patients with breast, lung, and prostate cancer and blastic bone metastases to either zoledronic acid (ZA) alone or ZA plus radiopharmaceuticals (Sr-89 or Sm-153). The primary endpoint was time to development of SREs. Secondary objectives included quality of life (QOL), pain control, overall survival (OS), and toxicity.Results261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued between July 2006 and February 2011. The study closed early due to a lower than expected rate of SREs. 52 (42%) patients in the ZA arm and 49 (40%) in the radiopharmaceutical arm experienced an SRE. Median time free of SREs was 29.9 and 27.4 months, respectively (p = 0.84). Median OS in the ZA arm and radiopharmaceutical arms was 32.1 and 26.9 months, respectively (p = 0.37). Cox proportional hazards regression model showed that primary disease site (lung) and number of bone metastases (> 2) had a negative impact on OS (p < 0.0001, p = 0.01, respectively). The addition of radiopharmaceuticals to ZA led to a significant reduction in pain at 1 month based on BPI worst score (p = 0.02). No other group differences were noted for QOL or toxicity.ConclusionThe addition of radiopharmaceuticals to bisphosphonates did not alter time to SREs or OS for patients with breast, lung, prostate cancers and blastic bone metastases, although it was associated with significant pain reduction at 1 month.Clinical Trial RegistryThis protocol (RTOG 0517) is registered with ClinicalTrials.gov (NCT00365105), and may be viewed online at http://www.clinicaltrials.gov/ct2/show/NCT00365105?term=RTOG+0517&rank=1.

Summary This study shows that teriparatide promotes the circulating osteoblast (OB) precursor degree of maturation in patients affected by postmenopausal osteoporosis. Introduction Anabolic treatment with teriparatide has proven effective for the therapy of postmenopausal osteoporosis and significantly reduces the risk of non-vertebral fragility fractures. The aim of this study was to investigate the effect of teriparatide on circulating OB precursors. Methods We evaluated by flow cytometry and real-time PCR the expression of OBs typical markers in peripheral blood mononuclear cells during treatment with teriparatide plus calcium and vitamin D, raloxifene plus calcium and vitamin D or calcium and vitamin D alone at various time points. Serum bone alkaline phosphatase and osteocalcin (OC) were measured as markers of bone turnover. Results Our results show that circulating OB precursors are more numerous and more immature in patients affected by fragility fractures than in osteoporotic patients without fractures. We also show that teriparatide treatment increases the expression of alkaline phosphatase and of OC in OB precursors; thus, it increases their degree of maturation. Conclusions We suggest that teriparatide acts as anabolic agents also by promoting the maturation of OB precursors.

Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.

A mouse model shows that osteoblast activating β-catenin mutations alone are sufficient to initiate the development of acute myeloid leukaemia acting through increased Notch signalling. Notch involvement in leukaemia The tumour microenvironment has profound influences on tumorigenesis, and genetic alterations in stromal cells can contribute to the development of cancer. Stavroula Kousteni and colleagues show in a mouse model that activating mutations in β-catenin in osteoblasts are sufficient to initiate the development of acute myeloid leukaemia (AML). These mutations trigger the release of ligands from osteoblasts that activate the Notch signalling pathway in haematopoietic cells; inhibition of the Notch pathway ameliorates the disease. The observation of increased β-catenin signalling in osteoblasts in patients with myeloproliferative disease and AML suggests that a similar mechanism may contribute to leukaemia in humans. Cells of the osteoblast lineage affect the homing 1 , 2 and the number of long-term repopulating haematopoietic stem cells 3 , 4 , haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis 5 , 6 , 7 . Osteoblasts were recently implicated in pre-leukaemic conditions in mice 8 , 9 . However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of β-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased β-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.

Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in the pathogenesis of osteoarthritis and osteoporosis. Chondrocyte proliferation, differentiation, and apoptosis are important steps for endochondral ossification. Although the inactivation of P53 and RB is involved in the pathogenesis of osteosarcomas, the deletion of p53 and inactivation of Rb are insufficient to enhance chondrocyte proliferation, indicating the presence of multiple inhibitory mechanisms against sarcomagenesis in chondrocytes. The inflammatory processes induced by mechanical injury and chondrocyte death through the release of danger-associated molecular patterns (DAMPs) are involved in the pathogenesis of posttraumatic osteoarthritis. The overexpression of BCLXL increases bone volume with a normal structure and maintains bone during aging by inhibiting osteoblast apoptosis. p53 inhibits osteoblast proliferation and enhances osteoblast apoptosis, thereby reducing bone formation, but also exerts positive effects on osteoblast differentiation through the Akt–FoxOs pathway. Apoptotic osteocytes release ATP, which induces the receptor activator of nuclear factor κ-B ligand (Rankl) expression and osteoclastogenesis, from pannexin 1 channels. Osteocyte death ultimately results in necrosis; DAMPs are released to the bone surface and promote the production of proinflammatory cytokines, which induce Rankl expression, and osteoclastogenesis is further enhanced.

Osteoporosis is widely regarded as one of the typical aging-related diseases due to the impairment of bone remodeling. The silent information regulator of transcription1 (SIRT1) is a vital regulator of cell survival and life-span. SIRT1 has been shown to be activated by resveratrol treatment, and also has been proved to prevent aging-related diseases such as osteoporosis. However, the role of SIRT1 about autophagy or mitophagy of osteoblasts in resveratrol-regulated osteoporotic rats remains unclear. This study seeks to investigate the role of SIRT1 about autophagy or mitophagy in osteoblasts through PI3K/Akt signaling pathway in resveratrol-regulated osteoporotic rats. The vivo experiment results have revealed that resveratrol treatment significantly improved bone quality and reduced the levels of serum alkaline phosphatase and osteocalcin in osteoporotic rats. Moreover, Western bolt analysis showed that expression of SIRT1, LC3, and Beclin-1 in osteoblasts increased, while p -AKT and p -mTOR were downregulated in osteoporosis rats with high dose resveratrol treatment. On the other hand, resveratrol treatment increased the SIRT1 activity, LC3 and Beclin-1 mRNA expression in the dexamethasone (DEX)-treated osteoblasts. More mitophagosomes were observed in the DEX-treated osteoblasts with resveratrol. Meanwhile, the TOM20, Hsp60, p -Akt and p -mTOR activities were decreased in the DEX-treated osteoblasts with resveratrol. Resveratrol treatment did not change the p -p38 and p -JNK activities in the osteoblasts. These results revealed that resveratrol treatment protected osteoblasts in osteoporosis rats by enhancing mitophagy by mediating SIRT1 and PI3K/AKT/mTOR signaling pathway.

Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.