Sclerostin does not play a major role in the pathogenesis of skeletal complications in type 2 diabetes mellitus

In contrast to previously reported elevations in serum sclerostin levels in diabetic patients, the present study shows that the impaired bone microarchitecture and cellular turnover associated with type 2 diabetes mellitus (T2DM)-like conditions in ZDF rats are not correlated with changes in serum and bone sclerostin expression. INTRODUCTION: T2DM is associated with impaired skeletal structure and a higher prevalence of bone fractures. Sclerostin, a negative regulator of bone formation, is elevated in serum of diabetic patients. We aimed to relate changes in bone architecture and cellular activities to sclerostin production in the Zucker diabetic fatty (ZDF) rat. METHODS: Bone density and architecture were measured by micro-CT and bone remodelling by histomorphometry in tibiae and femurs of 14-week-old male ZDF rats and lean Zucker controls (n = 6/group). RESULTS: ZDF rats showed lower trabecular bone mineral density and bone mass compared to controls, due to decreases in bone volume and thickness, along with impaired bone connectivity and cortical bone geometry. Bone remodelling was impaired in diabetic rats, demonstrated by decreased bone formation rate and increased percentage of tartrate-resistant acid phosphatase-positive osteoclastic surfaces. Serum sclerostin levels (ELISA) were higher in ZDF compared to lean rats at 9 weeks (+40 %, p < 0.01), but this difference disappeared as their glucose control deteriorated and by week 14, ZDF rats had lower sclerostin levels than control rats (-44 %, p < 0.0001). Bone sclerostin mRNA (qPCR) and protein (immunohistochemistry) were similar in ZDF, and lean rats at 14 weeks and genotype did not affect the number of empty osteocytic lacunae in cortical and trabecular bone. CONCLUSION: T2DM results in impaired skeletal architecture through altered remodelling pathways, but despite altered serum levels, it does not appear that sclerostin contributes to the deleterious effect of T2DM in rat bone

Excessive growth hormone expression in male GH transgenic mice adversely alters bone architecture and mechanical strength

Patients with acromegaly have a higher prevalence of vertebral fractures despite normal bone mineral density (BMD), suggesting that GH overexpression has adverse effects on skeletal architecture and strength. We used giant bovine GH (bGH) transgenic mice to analyze the effects of high serum GH levels on BMD, architecture, and mechanical strength. Five-month-old hemizygous male bGH mice were compared with age- and sex-matched nontransgenic littermates controls (NT; n=16/group). Bone architecture and BMD were analyzed in tibia and lumbar vertebrae using microcomputed tomography. Femora were tested to failure using three-point bending and bone cellular activity determined by bone histomorphometry. bGH transgenic mice displayed significant increases in body weight and bone lengths. bGH tibia showed decreases in trabecular bone volume fraction, thickness, and number compared with NT ones, whereas trabecular pattern factor and structure model index were significantly increased, indicating deterioration in bone structure. Although cortical tissue perimeter was increased in transgenic mice, cortical thickness was reduced. bGH mice showed similar trabecular BMD but reduced trabecular thickness in lumbar vertebra relative to controls. Cortical BMD and thickness were significantly reduced in bGH lumbar vertebra. Mechanical testing of femora confirmed that bGH femora have decreased intrinsic mechanical properties compared with NT ones. Bone turnover is increased in favor of bone resorption in bGH tibia and vertebra compared with controls, and serum PTH levels is also enhanced in bGH mice. These data collectively suggest that high serum GH levels negatively affect bone architecture and quality at multiple skeletal sites

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Some anti-diabetic therapies can have adverse effects on bone health and increase fracture risk. In this study, we tested the skeletal effects of chronic administration of two Glucagon-like peptide-1 receptor agonists (GLP-1RA), increasingly used for type 2 diabetes treatment, in a model of osteoporosis associated bone loss and examined the expression and activation of GLP-1R in bone cells. Mice were ovariectomised (OVX) to induce bone loss and four weeks later they were treated with Liraglutide (LIR) 0.3 mg/kg/day, Exenatide (Ex-4) 10 μg/kg/day or saline for four weeks. Mice were injected with calcein and alizarin red prior to euthanasia, to label bone-mineralising surfaces. Tibial micro-architecture was determined by micro-CT and bone formation and resorption parameters measured by histomorphometric analysis. Serum was collected to measure calcitonin and sclerostin levels, inhibitors of bone resorption and formation, respectively. GLP-1R mRNA and protein expression were evaluated in the bone, bone marrow and bone cells using RT-PCR and immunohistochemistry. Primary osteoclasts and osteoblasts were cultured to evaluate the effect of GLP-1RA on bone resorption and formation in vitro. GLP-1RA significantly increased trabecular bone mass, connectivity and structure parameters but had no effect on cortical bone. There was no effect of GLP-1RA on bone formation in vivo but an increase in osteoclast number and osteoclast surfaces was observed with Ex-4. GLP-1R was expressed in bone marrow cells, primary osteoclasts and osteoblasts and in late osteocytic cell line. Both Ex-4 and LIR stimulated osteoclastic differentiation in vitro but slightly reduced the area resorbed per osteoclast. They had no effect on bone nodule formation in vitro. Serum calcitonin levels were increased and sclerostin levels decreased by Ex-4 but not by LIR. Thus, GLP-1RA can have beneficial effects on bone and the expression of GLP-1R in bone cells may imply that these effects are exerted directly on the tissue

Non-invasive mechanical joint loading as an alternative model for osteoarthritic pain

OBJECTIVE: Mechanisms responsible for osteoarthritic pain remain poorly understood and current analgesic therapies are often insufficient. We have characterized and pharmacologically tested the pain phenotype of a non-invasive mechanical joint loading (MJL) model of osteoarthritis thus providing an alternative murine model for osteoarthritic pain. METHODS: The right knees of male mice (12-week-old, C57BL/6) were loaded at 9N or 11N (40 cycles, three times/week for two weeks). Behavioural measurements of limb disuse, mechanical and thermal hypersensitivity were acquired before MJL and monitored for six weeks post-loading. The severity of articular cartilage lesions was determined post-mortem with the OARSI grading scheme. Furthermore, 9N-loaded mice were treated for four weeks with diclofenac (10mg/kg), gabapentin (100mg/kg) or anti-Nerve Growth Factor (3mg/kg). RESULTS: Mechanical hypersensitivity and weight-bearing worsened significantly in 9N- and 11N-loaded mice two weeks post-loading compared to baseline values and non-loaded controls. Maximum OA scores of ipsilateral knees confirmed increased cartilage lesions in 9N- (2.8±0.2) and 11N-loaded (5.3±0.3) mice compared to non-loaded controls (1.0±0.0). Gabapentin and diclofenac restored pain behaviours to baseline values after two weeks of daily treatment, with gabapentin being more effective than diclofenac. A single injection of anti-NGF alleviated nociception two days after treatment and remained effective for two weeks with a second dose inducing stronger and more prolonged analgesia. CONCLUSION: Our results show that MJL induces OA lesions and a robust pain phenotype that can be reversed using analgesics known to alleviate OA pain in patients. This establishes the use of MJL as an alternative model for osteoarthritic pain

The 4 per 1000 initiative.

Soil organic matter is at the nexus of global challenges: food security, climate change adaptation and mitigation, soil security. The 4 per 1000 initiative, launched at the Climate COP21 within the Lima-Paris Action Agenda proposes to increase soil organic carbon (SOC) stocks to simultaneously address all these challenges. It directly addresses three sustainable development goals: SDG2 ?no hunger?, SDG13 ?Climate action?, and SDG15 ?Life on land? and indirectly concerns several others. The initiative targets agricultural soils in priority, which are often the most degraded soils and because of the high expected benefits in terms of soil fertility and hence of productivity. A range of agricultural practices are available that allow to increase SOC stocks while ensuring a resilient, productive and environmentally friendly agriculture, so that a large-scale deployment can be aimed at. Here, we review and discuss the main limits and criticisms addressed to the 4 per 1000 initiative

Full characterization of vibrational coherence in a porphyrin chromophore by two-dimensional electronic spectroscopy

In this work we present experimental and calculated two-dimensional electronic spectra for a 5,15-bisalkynyl porphyrin chromophore. The lowest energy electronic Qy transition couples mainly to a single 380 cm–1 vibrational mode. The two-dimensional electronic spectra reveal diagonal and cross peaks which oscillate as a function of population time. We analyze both the amplitude and phase distribution of this main vibronic transition as a function of excitation and detection frequencies. Even though Feynman diagrams provide a good indication of where the amplitude of the oscillating components are located in the excitation-detection plane, other factors also affect this distribution. Specifically, the oscillation corresponding to each Feynman diagram is expected to have a phase that is a function of excitation and detection frequencies. Therefore, the overall phase of the experimentally observed oscillation will reflect this phase dependence. Another consequence is that the overall oscillation amplitude can show interference patterns resulting from overlapping contributions from neighboring Feynman diagrams. These observations are consistently reproduced through simulations based on third order perturbation theory coupled to a spectral density described by a Brownian oscillator model

Multidecadal persistence of organic matter in soils: multiscale investigations down to the submicron scale

Minerals, particularly clay-sized minerals, protect soil organic matter (SOM) from decomposition by microorganisms. Here we report the characterization of SOM and the associated minerals over decades of biodegradation, in a French long-term bare fallow (LTBF) experiment started in 1928. The amounts of carbon (C) and nitrogen (N) in the study area declined over time for six fractions (sand, coarse silt, fine silt, coarse clays, intermediate clays, and fine clays). The C:N ratios of SOM associated with silt fractions remained constant, whereas the ratios significantly decreased in clays, reaching very low values in intermediate and fine clays (C:N&thinsp;&lt; 5) after 8 decades of LTBF conditions. X-ray absorption spectroscopy revealed the following: (i) bulk-scale SOM chemical speciation remained almost constant; (ii) submicron particulate OM was present in coarse clays, even after 79 years of LTBF conditions; and (iii) illite particles became progressively SOM-free with time, whereas mixed-layer illite/smectite and smectites were always associated with OM throughout the bare fallow treatment. In summary, these results suggest that clay-sized minerals preferentially protect N-rich SOM and that smectites and mixed-layer illite/smectite seem to protect associated OM more effectively than pure illites.</p

The moisture response of soil heterotrophic respiration: Interaction with soil properties

Soil moisture is of primary importance for predicting the evolution of soil carbon stocks and fluxes, both because it strongly controls organic matter decomposition and because it is predicted to change at global scales in the following decades. However, the soil functions used to model the heterotrophic respiration response to moisture have limited empirical support and introduce an uncertainty of at least 4% in global soil carbon stock predictions by 2100. The necessity of improving the representation of this relationship in models has been highlighted in recent studies. Here we present a data-driven analysis of soil moisture-respiration relations based on 90 soils. With the use of linear models we show how the relationship between soil heterotrophic respiration and different measures of soil moisture is consistently affected by soil properties. The empirical models derived include main effects and moisture interaction effects of soil texture, organic carbon content and bulk density. When compared to other functions currently used in different soil biogeochemical models, we observe that our results can correct biases and reconcile differences within and between such functions. Ultimately, accurate predictions of the response of soil carbon to future climate scenarios will require the integration of soil-dependent moisture-respiration functions coupled with realistic representations of soil water dynamic