COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay.

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.

Activation of ß-adrenergic receptor signaling prevents glucocorticoid-induced obesity and adipose tissue dysfunction in male mice.

Elevated serum concentrations of glucocorticoids (GCs) result in excessive lipid accumulation in white adipose tissue (WAT) as well as dysfunction of thermogenic brown adipose tissue (BAT), ultimately leading to the development of obesity and metabolic disease. Here, we hypothesized that activation of the sympathetic nervous system either via cold exposure or the use of a selective ß3-adrenergic receptor (ß3-AR) agonist alleviates the adverse metabolic effects of chronic GC exposure in rodents. To this end, male 10-wk-old C57BL/6NRj mice were treated with corticosterone via drinking water or placebo for 4 wk while being maintained at 29°C (thermoneutrality), 22°C (room temperature), or 13°C (cold temperature); in a follow-up study mice received a selective ß3-AR agonist or placebo with and without corticosterone while being maintained at room temperature. Body weight and food intake were monitored throughout the study. Histological and molecular analyses were performed on white and brown adipose depots. Cold exposure not only preserved the thermogenic function of brown adipose tissue but also reversed GC-induced lipid accumulation in white adipose tissue and corrected GC-driven obesity, hyperinsulinemia, and hyperglycemia. The metabolic benefits of cold exposure were associated with enhanced sympathetic activity in adipose tissue, thus potentially linking an increase in sympathetic signaling to the observed metabolic benefits. In line with this concept, chronic administration of a selective ß3-AR agonist reproduced the beneficial metabolic effects of cold adaption during exposure to exogenous GCs. This preclinical study demonstrates the potential of ß3-AR as a therapeutic target in the management and prevention of GC-induced metabolic disease.NEW & NOTEWORTHY This preclinical study in mice shows that the ß3-adrenergic receptor can be a potential therapeutic approach to counteracting glucocorticoid (GC)-induced obesity and metabolic dysfunction. Both cold acclimation and ß3-adrenergic receptor stimulation in a mouse model of excess glucocorticoids were adequate in not only preventing obesity, adiposity, and adipose tissue dysfunction but also correcting hyperinsulinemia, hyperleptinemia, and dyslipidemia.

A global Slc7a7 knockout mouse model demonstrates characteristic phenotypes of human lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7Lbu/Lbu and Slc7a7Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7Lbu/Lbu mice exhibited reduced plasma and increased urinary concentrations of the cationic amino acids. Histopathological assessment revealed loss of brush border and lipid vacuolation in the renal cortex of Slc7a7Lbu/Lbu mice, which combined with aminoaciduria suggests proximal tubular dysfunction. Micro-computed tomography of L4 vertebrae and skeletal radiographs showed delayed skeletal development and suggested decreased mineralization in Slc7a7Lbu/Lbu mice, respectively. In addition to delayed skeletal development and delayed development in the kidneys, the lungs and liver were observed based on histopathological assessment. Overall, our Slc7a7Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.

A multicenter study to evaluate pulmonary function in osteogenesis imperfecta.

Pulmonary complications are a significant cause for morbidity and mortality in osteogenesis imperfecta (OI). However, to date, there have been few studies that have systematically evaluated pulmonary function in individuals with OI. We analyzed spirometry measurements, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1 ), in a large cohort of individuals with OI (n = 217) enrolled in a multicenter, observational study. We show that individuals with the more severe form of the disease, OI type III, have significantly reduced FVC and FEV1 which do not follow the expected trends of the normal population. We also show that "normalization" of FVC and FEV1 using general population data to generate percent predicted values underestimates the pulmonary involvement in OI. Within each subtype of OI, we used linear mixed models to find potential correlations between FEV1 and FVC with the clinical variables including mobility, bisphosphonate use, and scoliosis. Our results are an important step in understanding the extent of pulmonary involvement in individuals with OI and for developing pulmonary endpoints for use in the routine patient care as well as in the investigation of new therapies.

Differential effects of collagen prolyl 3-hydroxylation on skeletal tissues.

Mutations in the genes encoding cartilage associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1 encoded by LEPRE1) were the first identified causes of recessive Osteogenesis Imperfecta (OI). These proteins, together with cyclophilin B (encoded by PPIB), form a complex that 3-hydroxylates a single proline residue on the α1(I) chain (Pro986) and has cis/trans isomerase (PPIase) activity essential for proper collagen folding. Recent data suggest that prolyl 3-hydroxylation of Pro986 is not required for the structural stability of collagen; however, the absence of this post-translational modification may disrupt protein-protein interactions integral for proper collagen folding and lead to collagen over-modification. P3H1 and CRTAP stabilize each other and absence of one results in degradation of the other. Hence, hypomorphic or loss of function mutations of either gene cause loss of the whole complex and its associated functions. The relative contribution of losing this complex's 3-hydroxylation versus PPIase and collagen chaperone activities to the phenotype of recessive OI is unknown. To distinguish between these functions, we generated knock-in mice carrying a single amino acid substitution in the catalytic site of P3h1 (Lepre1(H662A) ). This substitution abolished P3h1 activity but retained ability to form a complex with Crtap and thus the collagen chaperone function. Knock-in mice showed absence of prolyl 3-hydroxylation at Pro986 of the α1(I) and α1(II) collagen chains but no significant over-modification at other collagen residues. They were normal in appearance, had no growth defects and normal cartilage growth plate histology but showed decreased trabecular bone mass. This new mouse model recapitulates elements of the bone phenotype of OI but not the cartilage and growth phenotypes caused by loss of the prolyl 3-hydroxylation complex. Our observations suggest differential tissue consequences due to selective inactivation of P3H1 hydroxylase activity versus complete ablation of the prolyl 3-hydroxylation complex.

Pharmacological and biological therapeutic strategies for osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility, low bone mass, and bone deformities. The majority of cases are caused by autosomal dominant pathogenic variants in the COL1A1 and COL1A2 genes that encode type I collagen, the major component of the bone matrix. The remaining cases are caused by autosomal recessively or dominantly inherited mutations in genes that are involved in the post-translational modification of type I collagen, act as type I collagen chaperones, or are members of the signaling pathways that regulate bone homeostasis. The main goals of treatment in OI are to decrease fracture incidence, relieve bone pain, and promote mobility and growth. This requires a multi-disciplinary approach, utilizing pharmacological interventions, physical therapy, orthopedic surgery, and monitoring nutrition with appropriate calcium and vitamin D supplementation. Bisphosphonate therapy, which has become the mainstay of treatment in OI, has proven beneficial in increasing bone mass, and to some extent reducing fracture risk. However, the response to treatment is not as robust as is seen in osteoporosis, and it seems less effective in certain types of OI, and in adult OI patients as compared to most pediatric cases. New pharmacological treatments are currently being developed, including anti-resorptive agents, anabolic treatment, and gene- and cell-therapy approaches. These therapies are under different stages of investigation from the bench-side, to pre-clinical and clinical trials. In this review, we will summarize the recent findings regarding the pharmacological and biological strategies for the treatment of patients with OI. © 2016 Wiley Periodicals, Inc.

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-ß in the bone microenvironment.

TGF-ß is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-ß bioavailability by attenuating maturation of pro-TGF-ß during cartilage homeostasis. However, whether regulation of intracellular TGF-ß maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1(-/-) mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1(-/-) osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1(-/-) osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast-osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1(-/-) calvaria exhibit an elevated mature TGF-ß/pro-TGF-ß ratio, with increased expression of TGF-ß downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan-TGF-ß antibody, significantly improved the low bone mass of Esl-1(-/-) mice, suggesting that elevated TGF-ß signaling is the major cause of osteopenia in Esl-1(-/-) mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-ß maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast-osteoclast coupling.

Kyphoplasty in patients with multiple myeloma a retrospective comparative pilot study.

BACKGROUND: This retrospective study of 73 myeloma patients with painful vertebral lesions compares clinical and radiomorphological outcomes up to 2 years after additional kyphoplasty, radiation therapy or systemic treatment only. METHODS: We assessed pain, disability and radiomorphological parameters by visual analogue scale (VAS 0-100), Oswestry Disability Index and by re-evaluating available follow-up X-rays, respectively, in patients that were treated according to a clinical pathway. RESULTS: After 2 years the VAS score was reduced in all groups by 66 ± 8.2 (kyphoplasty), 35 ± 10.5 (radiation therapy) and 38 ± 20.5 (systemic therapy only). Only after kyphoplasty we observed a significantly reduced Oswestry Disability Index after 1 year (P < 0.001). Vertebral height remained stable after kyphoplasty (P = 0.283), in contrast to a progressive height loss in the other groups (P = 0.013 and P = 0.015 for radiation and systemic therapy only, respectively). Two years after kyphoplasty and radiotherapy the overall vertebral fracture incidence was significantly decreased as compared to the group after systemic therapy only (9.7% of all thoracic and lumbar vertebrae had new vertebral fractures after systemic therapy only, 2% after kyphoplasty (P < 0.001), 4.8% after radiation (P = 0.032)). CONCLUSION: Additional kyphoplasty was more effective than additional radiation or systemic therapy in terms of pain relief, reduction of pain associated disability and reduction of fracture incidence of the entire lumbar and thoracic spine.

Targeting TGF-ß for treatment of osteogenesis imperfecta.

BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-ß signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-ß signaling in children with OI and conducted a phase I clinical trial of TGF-ß inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-ß neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-ß pathway as the top activated signaling pathway, and IPA showed that TGF-ß1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-ß signaling is a driver pathogenic mechanism in OI. Anti-TGF-ß therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

Osteoplastic procedures for the treatment of vertebral complications in multiple myeloma patients.

Pain induced by vertebral fracture in multiple myeloma can be treated by an osteoplastic procedure. The magnitude of the pain reduction by the procedure depends on the presence of additional causes for pain as spondylosis deformans, osteochondrosis, stenosis of the spinal canal, or intervertebral nerve compression. To identify additional reasons for pain apart from a vertebral fracture-induced pain, a detailed preoperative analysis of the patients complaints is crucial for the outcome after an osteoplastic procedure. In addition, the technical aspects for performing the procedure and potential complications have to be considered as well as the stability of the cortical bone of the respective vertebral body. A complete collapse of the vertebra (vertebra plana) is an unfavorable situation for any osteoplastic procedure. In case of inflammatory or infectious vertebral lesions (e.g. spondylodiscitis) osteoplastic procedures are contraindicated. An interdisciplinary discussion of the individual case among oncologists, radiotherapists, trauma/spien surgeons, radiologists, and osteologists/endocrinologists is a prerequisite for the identification of patients who will truly benefit from an osteoplastic procedure and to avoid overtreatment of the patient and economical exploitation of healthcare providers.

Three-year outcomes after kyphoplasty in patients with osteoporosis with painful vertebral fractures.

PURPOSE: Kyphoplasty immediately improves pain and mobility in patients with painful osteoporotic vertebral fractures, but long-term clinical outcomes are still unclear. This controlled trial evaluates pain, mobility and fracture incidence 3 years after kyphoplasty. MATERIALS AND METHODS: Kyphoplasty was performed in 40 patients with painful osteoporotic vertebral fractures; 20 patients who were selected for kyphoplasty but chose not to undergo the procedure served as controls. All patients received pharmacologic antiosteoporosis treatment, pain medication, and physiotherapy. Pain (visual analog scale of 0-100), mobility (European Vertebral Osteoporosis Study questionnaire score of 0-100), and incident vertebral fractures were assessed at baseline, postprocedurally, and after 12 and 36 months. RESULTS: Pain score improved after kyphoplasty from 73.8 to 55.9 (immediately after kyphoplasty), 55.6 (12 months), and 54.0 (36 months; P < .001). Pain score in the control group changed from 66.4 to 65.7 at 12 months and 64.0 at 36 months (P = .521). The pain score of the kyphoplasty group was significantly improved versus controls after 36 months (P = .023). Mobility score improved after kyphoplasty from 43.8 to 54.2 (immediately after kyphoplasty), 54.5 (12 months), and 54.8 (36 months; P = .0008) and remained increased (P = .308) compared with controls (39.8 immediately after kyphoplasty, 44.3 at 12 months, and 43.6 at 36 months). The incidence of new vertebral fractures after kyphoplasty was significantly reduced versus controls after 3 years (P = .0341). CONCLUSIONS: Kyphoplasty reduces pain and improves mobility as long as 3 years after the procedure. The long-term risk of new vertebral fractures after kyphoplasty of chronically painful vertebral fractures is reduced versus controls.

Direct effects of osteoprotegerin on human bone cell metabolism.

PURPOSE: Osteoprotegerin (OPG) affects bone metabolism by intercepting the RANK-RANKL interaction which prevents osteoclastic differentiation and consequently reduces bone resorption. Different bone phenotypes of mice overexpressing OPG and of mice with knockdown of receptor activator of NF-kappaB (RANK) or RANK-ligand (RANKL) suggest that the mechanism of action of the OPG-RANKL-RANK system in regulating bone remodeling is not completely understood. Furthermore, OPG increases bone mass and density independently from reduced osteoclastogenesis which is consistent with the possibility that OPG may directly affect bone metabolism beyond its known role as decoy receptor for RANKL. METHODS: We treated primary human osteoblastic cells with OPG and inhibitory anti-RANKL antibodies and measured cellular ALP activity, in vitro mineralization, vitronectin receptor protein expression and ERK phosphorylation. We also analyzed the mRNA co-expression of ALP and OPG ex vivo in bone biopsies from acute and old stable vertebral fractures. RESULTS: OPG directly increased ALP activity and in vitro mineralization of HOC, enhanced expression of the vitronectin receptor thereby increasing adherence of HOC to vitronectin and stimulated ERK phosphorylation. All OPG-mediated effects could be prevented by RANKL antibodies or RANKL-siRNA transfection and MAPK inhibitor PD98059 reduced the stimulatory effect of OPG on integrin alphav expression. In acutely fractured vertebrae OPG and ALP mRNA expression was significantly increased compared to stable vertebral fractures. In conclusion, OPG exerts direct osteoanabolic effects on HOC metabolism via RANKL in addition to its well described role as decoy receptor for RANKL.

Transient post-operative thyrotoxicosis after parathyroidectomy.

BACKGROUND: Secondary and tertiary hyperparathyroidism are features of chronic renal disease. Although pharmacological options are available, parathyroid surgery remains the treatment of choice in these patients with worsening renal osteodystrophy or hypercalcemia. The development of thyrotoxicosis after parathyroid surgery in these patients has been rarely reported. CASE REPORT: We report a 33 years old woman who developed transient symptomatic thyrotoxicosis following parathyroid surgery for tertiary hyperparathyroidism. Laboratory and imaging studies were consistent with postoperative hyperthyroidism due to thyroiditis. CONCLUSIONS: Transient hyperthyroidism may occur after parathyroidectomy presumably due to a traumatic thyroiditis as a result of manipulation of the thyroid gland during surgery. As it is transient, thyrostatic therapy is not indicated but patients may require short-term treatment with beta-blockers for symptomatic relief.

Identification of Functionally Distinct Mx1+αSMA+ Periosteal Skeletal Stem Cells.

The periosteum is critical for bone maintenance and healing. However, the in vivo identity and specific regulatory mechanisms of adult periosteum-resident skeletal stem cells are unknown. Here, we report animal models that selectively and durably label postnatal Mx1+αSMA+ periosteal stem cells (P-SSCs) and establish that P-SSCs are a long-term repopulating, functionally distinct SSC subset responsible for lifelong generation of periosteal osteoblasts. P-SSCs rapidly migrate toward an injury site, supply osteoblasts and chondrocytes, and recover new periosteum. Notably, P-SSCs specifically express CCL5 receptors, CCR3 and CCR5. Real-time intravital imaging revealed that the treatment with CCL5 induces P-SSC migration in vivo and bone healing, while CCL5/CCR5 deletion, CCR5 inhibition, or local P-SSC ablation reduces osteoblast number and delays bone healing. Human periosteal cells express CCR5 and undergo CCL5-mediated migration. Thus, the adult periosteum maintains genetically distinct SSC subsets with a CCL5-dependent migratory mechanism required for bone maintenance and injury repair.

TGF-ß Family Signaling in Mesenchymal Differentiation.

Mesenchymal stem cells (MSCs) can differentiate into several lineages during development and also contribute to tissue homeostasis and regeneration, although the requirements for both may be distinct. MSC lineage commitment and progression in differentiation are regulated by members of the transforming growth factor-ß (TGF-ß) family. This review focuses on the roles of TGF-ß family signaling in mesenchymal lineage commitment and differentiation into osteoblasts, chondrocytes, myoblasts, adipocytes, and tenocytes. We summarize the reported findings of cell culture studies, animal models, and interactions with other signaling pathways and highlight how aberrations in TGF-ß family signaling can drive human disease by affecting mesenchymal differentiation.

Genetic causes and mechanisms of Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by various clinical features including bone deformities, low bone mass, brittle bones, and connective tissue manifestations. The predominant cause of OI is due to mutations in the two genes that encode type I collagen. However, recent advances in sequencing technology has led to the discovery of novel genes that are implicated in recessive and dominant OI. These include genes that regulate the post-translational modification, secretion and processing of type I collagen as well as those required for osteoblast differentiation and bone mineralization. As such, OI has become a spectrum of genetic disorders informing about the determinants of both bone quantity and quality. Here we summarize the known genetic causes of OI, animal models that recapitulate the human disease and mechanisms that underlie disease pathogenesis. Additionally, we discuss the effects of disrupted collagen networks on extracellular matrix signaling and its impact on disease progression.

Correlations Between Bone Mechanical Properties and Bone Composition Parameters in Mouse Models of Dominant and Recessive Osteogenesis Imperfecta and the Response to Anti-TGF-ß Treatment.

Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by brittle bones that are prone to fracture. Although previous studies in animal models investigated the mechanical properties and material composition of OI bone, little work has been conducted to statistically correlate these parameters to identify key compositional contributors to the impaired bone mechanical behaviors in OI. Further, although increased TGF-ß signaling has been demonstrated as a contributing mechanism to the bone pathology in OI models, the relationship between mechanical properties and bone composition after anti-TGF-ß treatment in OI has not been studied. Here, we performed follow-up analyses of femurs collected in an earlier study from OI mice with and without anti-TGF-ß treatment from both recessive (Crtap-/- ) and dominant (Col1a2+/P.G610C ) OI mouse models and WT mice. Mechanical properties were determined using three-point bending tests and evaluated for statistical correlation with molecular composition in bone tissue assessed by Raman spectroscopy. Statistical regression analysis was conducted to determine significant compositional determinants of mechanical integrity. Interestingly, we found differences in the relationships between bone composition and mechanical properties and in the response to anti-TGF-ß treatment. Femurs of both OI models exhibited increased brittleness, which was associated with reduced collagen content and carbonate substitution. In the Col1a2+/P.G610C femurs, reduced hydroxyapatite crystallinity was also found to be associated with increased brittleness, and increased mineral-to-collagen ratio was correlated with increased ultimate strength, elastic modulus, and bone brittleness. In both models of OI, regression analysis demonstrated that collagen content was an important predictor of the increased brittleness. In summary, this work provides new insights into the relationships between bone composition and material properties in models of OI, identifies key bone compositional parameters that correlate with the impaired mechanical integrity of OI bone, and explores the effects of anti-TGF-ß treatment on bone-quality parameters in these models. © 2016 American Society for Bone and Mineral Research.

Osteointegration and Resorption of Intravertebral and Extravertebral Calcium Phosphate Cement.

STUDY DESIGN: Eleven patients with painful osteoporotic vertebral fractures who underwent kyphoplasty using calcium phosphate (CaP) cement were followed up for 1 week, 1, 2, and 3 years in a monocentric, nonrandomized, noncontrolled retrospective trial. OBJECTIVE: This study investigates long-term radiomorphologic features of intraosseous CaP cement implants and of extraosseous CaP cement leakages for up to 3 years after implantation by kyphoplasty. SUMMARY OF BACKGROUND DATA: Kyphoplasty is frequently used for the treatment of painful osteoporotic fractures. Of the materials available, CaP is frequently used as a filling material. Resorption of this material is frequently observed, although clinical outcome is comparable with other cements. METHODS: Kyphoplasty utilizing CaP cement was performed in 11 patients with painful osteoporotic vertebral fractures. All patients received a pharmacological antiosteoporosis treatment consisting of calcium, vitamin D, and a standard dose of oral bisphosphonates. Radiomorphologic measurements, pain, and mobility were assessed. RESULTS: Intraosseous and extraosseous CaP cement volumes decreased significantly over 3 years. However, vertebral stability as determined by a constant vertebral body height and the sagittal index was not impaired. Pain improved significantly 2 years after implantation and the mobility scores 1 year after kyphoplasty at least until the third year. CONCLUSIONS: Intravertebral CaP cement implants are resorbed slowly over time without jeopardizing stability and clinical outcomes most likely because of a slowly progressing osseous replacement. Extraosseous CaP cement material because of leakages during the kyphoplasty procedure is almost completely resorbed as early as 2 years after the leakage occurred. Therefore, CaP cement is an important alternative to PMMA-based cement materials utilized for kyphoplasty of osteoporotic vertebral fractures.

Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone.

Osteogenesis imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical features including low bone mass, fractures, and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65-kDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that Fkbp10 expression is limited to bone, tendon, and ligaments in postnatal tissues. Furthermore, in both patients and Fkbp10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of Fkbp10, we conditionally ablated FKBP65 in Fkbp10fl/fl mice (Mus musculus; C57BL/6) using the osteoblast-specific Col1a1 2.3-kb Cre recombinase. Using µCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy (MS) of bone collagen demonstrated a decrease in mature, hydroxylysine-aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral-to-matrix ratio and in crystal size as shown by Raman spectroscopy and small-angle X-ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild-type littermates. Taken together, these data suggest that the altered collagen crosslinking through Fkbp10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton. © 2017 American Society for Bone and Mineral Research.

[Therapeutic management of acromegaly]. / Therapeutisches Management bei der Akromegalie.

BACKGROUND: Only 60% of the patients with acromegaly are biochemically cured (growth hormone [GH] nadir < 1.0 microg/l after an oral glucose load, normalized age- and gender-matched insulin-like growth factor-1 [IGF-1] levels) after transsphenoidal surgery of the pituitary gland. In the absence of a remission there are effective pharmacological treatment regimens available which are able to lower GH and IGF-1 serum levels. THERAPEUTIC STRATEGIES: Somatostatin analogs, a GH receptor antagonist and dopamine agonists have been shown to alleviate the comorbid features and to normalize GH and IGF-1 levels. CASE REPORTS: In this overview six case reports are presented to highlight the current pharmacological treatment options and to propose an algorithm for the clinical routine in patients with persisting acromegaly. CONCLUSION: Transsphenoidal surgery is the treatment of choice for the initial management of acromegaly. In the absence of a remission there are effective pharmacological treatment regimens available among which somatostatin analogs are recommended as the first-line treatment.