Combinatorial Inhibition of Myostatin and Activin A Improves Femoral Bone Properties in the G610C Mouse Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a collagen-related bone disorder characterized by fragile osteopenic bone and muscle weakness. We have previously shown that the soluble activin receptor type IIB decoy (sActRIIB) molecule increases muscle mass and improves bone strength in the mild to moderate G610C mouse model of OI. The sActRIIB molecule binds multiple transforming growth factor-β (TGF-β) ligands, including myostatin and activin A. Here, we investigate the musculoskeletal effects of inhibiting activin A alone, myostatin alone, or both myostatin and activin A in wild-type (Wt) and heterozygous G610C (+/G610C) mice using specific monoclonal antibodies. Male and female Wt and +/G610C mice were treated twice weekly with intraperitoneal injections of monoclonal control antibody (Ctrl-Ab, Regn1945), anti-activin A antibody (ActA-Ab, Regn2476), anti-myostatin antibody (Mstn-Ab, Regn647), or both ActA-Ab and Mstn-Ab (Combo, Regn2476, and Regn647) from 5 to 16 weeks of age. Prior to euthanasia, whole body composition, metabolism and muscle force generation assessments were performed. Post euthanasia, hindlimb muscles were evaluated for mass, and femurs were evaluated for changes in microarchitecture and biomechanical strength using micro–computed tomography (μCT) and three-point bend analyses. ActA-Ab treatment minimally impacted the +/G610C musculoskeleton, and was detrimental to bone strength in male +/G610C mice. Mstn-Ab treatment, as previously reported, resulted in substantial increases in hindlimb muscle weights and overall body weights in Wt and male +/G610C mice, but had minimal skeletal impact in +/G610C mice. Conversely, the Combo treatment outperformed ActA-Ab alone or Mstn-Ab alone, consistently increasing hindlimb muscle and body weights regardless of sex or genotype and improving bone microarchitecture and strength in both male and female +/G610C and Wt mice. Combinatorial inhibition of activin A and myostatin more potently increased muscle mass and bone microarchitecture and strength than either antibody alone, recapturing most of the observed benefits of sActRIIB treatment in +/G610C mice. © 2022 American Society for Bone and Mineral Research (ASBMR).     

营养和激素对家蝇卵黄发生的影响

本实验通过对家蝇取食量的测定，对家蝇进行不同饲料饲喂后，对其不同发育期的血淋巴、脂肪体及和卵巢的发育及卵黄蛋白含量进行观察测定，结果表明，取食蛋白组家蝇血淋巴、脂肪体和卵巢卵黄蛋白含量均高于奶粉组和对照组；羽化４８ｈ后的血淋巴和脂肪体中卵黄蛋白含量为７．３μｇ／μｌ、３１．９μｇ／头；卵巢卵黄蛋白含量为５５．０μｇ／头；在羽化后７２ｈ血淋巴和脂肪体中卵黄蛋白含量分别为２．９μｇ／μｌ、３２．０μｇ／头；卵巢卵黄蛋白含量为８０．０μｇ／头；脉冲式饲喂家蝇后，体内卵黄蛋白含量明显高于对照组，说明蛋白质饲料在家蝇卵黄发生中起重要作用。激素处理结果证明，ＪＨＡ单独处理及ＪＨＡ和蜕皮素协同处理均能促进卵黄蛋白的合成和摄取，而蜕皮素单独处理没有促进作用。最后对营养和激素对生殖的调控作用进行了讨论。     

Quasi-reversible two-electron reduction of oxygen at iodine submonolayer-coated gold electrode in alkaline media

Oxygen reduction reaction (ORR) was investigated using polycrystalline gold (Au (poly)) electrode modified with chemisorbed iodine (I_(ads)) submonolayer (sub I_(ads)) in O₂-saturated 0.1 M KOH solution. The sub I_(ads) was tailored by potential-dependent partial reductive desorption of I_(ads) from its full monolayer. The Au (1 1 1) facet of the Au (poly) electrode was considered to remain bared at the sub I_(ads)/Au (poly) electrode. The interesting finding of the present study is that (unlike the bare Au (poly) electrode) the sub I_(ads)/Au (poly) electrode exhibited a quasi-reversible two-electron reduction of O₂ in alkaline media. The probable origin of the observed quasi-reversible behavior of the ORR is discussed. Experimental investigations were performed using cyclic and steady-state voltammetric, amperometric and coulometric techniques.     

Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab

Pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancers and various eye diseases. However, little information is currently available on the binding kinetics and relative biological activity of various VEGF inhibitors. Therefore, we have evaluated the binding kinetics of two anti-VEGF antibodies, ranibizumab and bevacizumab, and VEGF Trap (also known as aflibercept), a novel type of soluble decoy receptor, with substantially higher affinity than conventional soluble VEGF receptors. VEGF Trap bound to all isoforms of human VEGF-A tested with subpicomolar affinity. Ranibizumab and bevacizumab also bound human VEGF-A, but with markedly lower affinity. The association rate for VEGF Trap binding to VEGF-A was orders of magnitude faster than that measured for bevacizumab and ranibizumab. Similarly, in cell-based bioassays, VEGF Trap inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A induced calcium mobilization and migration in human endothelial cells more potently than ranibizumab or bevacizumab. Only VEGF Trap bound human PlGF and VEGF-B, and inhibited VEGFR1 activation and HUVEC migration induced by PlGF. These data differentiate VEGF Trap from ranibizumab and bevacizumab in terms of its markedly higher affinity for VEGF-A, as well as its ability to bind VEGF-B and PlGF.     

Cortical Bone Porosity in Rabbit Models of Osteoporosis

Cortical bone porosity is intimately linked with remodeling, is of growing clinical interest, and is increasingly accessible by imaging. Thus, the potential of animal models of osteoporosis (OP) to provide a platform for studying how porosity develops and responds to interventions is tremendous. To date, rabbit models of OP have largely focused on trabecular microarchitecture or bone density; some such as ovariectomy (OVX) have uncertain efficacy and cortical porosity has not been extensively reported. Our primary objective was to characterize tibial cortical porosity in rabbit-based models of OP, including OVX, glucocorticoids (GC), and OVX + GC relative to controls (SHAM). We sought to: (i) test the hypothesis that intracortical remodeling is elevated in these models; (ii) contrast cortical remodeling and porosity in these models with that induced by parathyroid hormone (1–34; PTH); and (iii) contrast trabecular morphology in the proximal tibia across all groups. Evidence that an increase in cortical porosity occurred in all groups was observed, although this was the least robust for GC. Histomorphometric measures supported the hypothesis that remodeling rate was elevated in all groups and also revealed evidence of uncoupling of bone resorption and formation in the GC and OVX + GC groups. For trabecular bone, a pattern of loss was observed for OVX, GC, and OVX + GC groups, whereas the opposite was observed for PTH. Change in trabecular number best explained these patterns. Taken together, the findings indicated rabbit models provide a viable and varied platform for the study of OP and associated changes in cortical remodeling and porosity. Intriguingly, the evidence revealed differing effects on the cortical and trabecular envelopes for the PTH model. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..     

Hemorrhagic cystitis as an unexpected adverse reaction to temozolomide: case report

A case is reported in which temozolomide, a promising new DNA alkylating agent, was successfully used to treat radiation refractory metastatic brain tumors arising from primary breast cancer. However, the treatment had to be terminated after the second round of treatment due to the development of hemorrhagic cystitis. This side effect was totally unexpected. Another class of alkylating agents (cyclophosphamide and related compounds) exhibits this side effect caused by a prevalent acrolein metabolite. Temozolomide and its sister compounds, dacarbazine and 5-(3-methyltriazen-1-yl)imidazole-4-caroxamide, have never been reported to have this adverse reaction. This case serves to alert physicians to the existence of a possible subpopulation of patients who may experience hemorrhagic cystitis on treatment with imidazotetrazines by a mechanism that is yet to be established.     

Bone microstructure and bone mineral density are not systemically different in Antarctic icefishes and related Antarctic notothenioids

Ancestors of the Antarctic icefishes (family Channichthyidae) were benthic and had no swim bladder, making it energetically expensive to rise from the ocean floor. To exploit the water column, benthopelagic icefishes were hypothesized to have evolved a skeleton with “reduced bone,” which gross anatomical data supported. Here, we tested the hypothesis that changes to icefish bones also occurred below the level of gross anatomy. Histology and micro-CT imaging of representative craniofacial bones (i.e., ceratohyal, frontal, dentary, and articular) of extant Antarctic fish species specifically evaluated two features that might cause the appearance of “reduced bone”: bone microstructure (e.g., bone volume fraction and structure linear density) and bone mineral density (BMD, or mass of mineral per volume of bone). Measures of bone microstructure were not consistently different in bones from the icefishes Chaenocephalus aceratus and Champsocephalus gunnari, compared to the related benthic notothenioids Notothenia coriiceps and Gobionotothen gibberifrons. Some quantitative measures, such as bone volume fraction and structure linear density, were significantly increased in some icefish bones compared to homologous bones of non-icefish. However, such differences were rare, and no microstructural measures were consistently different in icefishes across all bones and species analyzed. Furthermore, BMD was similar among homologous bones of icefish and non-icefish Antarctic notothenioids. In summary, “reduced bone” in icefishes was not due to systemic changes in bone microstructure or BMD, raising the prospect that “reduced bone” in icefish occurs only at the gross anatomic level (i.e., smaller or fewer bones). Given that icefishes exhibit delayed skeletal development compared to non-icefish Antarctic fishes, combining these phenotypic data with genomic data might clarify genetic changes driving skeletal heterochrony.