Impact of adolescent intermittent ethanol exposure on interneurons and their surrounding perineuronal nets in adulthood

AUTHORS

Carol A. Dannenhoffer, Alexander Gómez-A, Victoria A. Macht, Rayyanoor Jawad, E. Blake Sutherland, Ryan P. Vetreno, Fulton T. Crews, Charlotte A. Boettiger, Donita L. Robinson

ABSTRACT

Background Binge alcohol exposure during adolescence results in long-lasting alterations in brain and behavior. For example, adolescent intermittent ethanol (AIE) exposure in rodents results in long-term loss of functional connectivity among prefrontal cortex (PFC) and striatal regions as well as a variety of neurochemical, molecular, and epigenetic alterations. Interneurons in the PFC and striatum play critical roles in behavioral flexibility and functional connectivity. For example, parvalbumin (PV) interneurons are known to contribute to neural synchrony, and cholinergic interneurons contribute to strategy selection. Furthermore, extracellular perineuronal nets (PNNs) surround some interneurons, particularly PV+ interneurons, to further regulate cellular plasticity. The effect of AIE exposure on expression of these markers within the PFC is not well understood.

Methods The present study tested the hypothesis that AIE exposure reduces expression of PV+ and ChAT+ interneurons in the adult PFC and striatum and increases related expression of PNNs (marked by binding of Wisteria Floribunda agglutinin lectin; WFA) in adulthood. Male rats were exposed to AIE (5 g/kg/day, 2-days-on/2-days-off, i.g., P25-P54) or water (CON), and brain tissue was harvested in adulthood (> P80). Immunohistochemistry and co-immunofluorescence were used to assess expression of ChAT, PV, and WFA labeling within the adult PFC and striatum following AIE exposure.

Results ChAT and PV interneuron numbers in the striatum and PFC were unchanged after AIE exposure. However, WFA labeling in the PFC of AIE-exposed rats was increased compared to CON rats. Moreover, significantly more PV neurons were surrounded by WFA labeling in AIE-exposed subjects relative to controls in both PFC subregions assessed: the orbitofrontal cortex (CON = 34%; AIE = 40%) and the medial PFC (CON = 10%; AIE = 14%).

Conclusions These findings indicate that while PV interneuron expression in the adult PFC and striatum is unaltered following AIE exposure, PNNs surrounding these neurons (indicated by extracellular WFA binding) are increased. This increase in PNNs may restrict plasticity of the ensheathed neurons, thus contributing to impaired microcircuitry in frontostriatal connectivity and related behavioral impairments.

Bacterial infections exacerbate myeloma bone disease

AUTHORS

Rui Liu, Yuping Zhong, Rui Chen, Shiyi Chen, Yazhu Huang & Huan Liu

ABSTRACT

Multiple myeloma is characterized by osteolytic lesions caused by reduced bone formation and activated bone resorption. An important feature of myeloma is a failure of bone healing after successful treatment. In this work, clinical studies indicated a highly positive correlation between bone marrow bacteria abundance and bone lesion numbers of myeloma patients in complete remission. Coculture experiments demonstrated that marrow Escherichia coli (E. coli) promotes osteoclast differentiation and inhibits osteoblast differentiation. Mechanism studies showed that E. coli lipopolysaccharides (LPS) activated NF-κB p65 signaling and reduced phosphorylated smad1/5/9 binding ability with RUNX2 promoter, leading to decreased RUNX2 expression in osteoblast progenitors. Additionally, LPS enhanced phosphorylated NF-κB p65 binding ability with NFATc1 promoter, leading to increased NFATc1 expression in osteoclast progenitors. In vivo studies revealed E. coli contributes to osteolytic bone lesion, and elimination of E. coli infection assists healing of bone lesion in mouse model of myeloma in complete remission. These findings establish a heretofore unrecognized effect for E. coli in the genesis of myeloma bone disease and suggest a new treatment strategy.

Association between bone mineral metabolism and vascular calcification in end-stage renal disease

AUTHORS

Louise Aaltonen, Niina Koivuviita, Marko Seppänen, Heikki Kröger, Xiaoyu Tong, Eliisa Löyttyniemi & Kaj Metsärinne

ABSTRACT

Background

Development of vascular calcification is accelerated in patients with end-stage renal disease. In addition to traditional risk factors of cardiovascular disease (CVD) abnormal bone and mineral metabolism together with many other factors contribute to the excess cardiovascular burden in patients on dialysis. Aortic calcification score and coronary calcification score are predictive of CVD and mortality. The aim of this study was to evaluate the possible relationship between arterial calcification and bone metabolism.

Methods

Thirty two patients on dialysis were included. All patients underwent a bone biopsy to assess bone histomorphometry and a 18F-NaF PET scan. Fluoride activity was measured in the lumbar spine (L1 – L4) and at the anterior iliac crest. Arterial calcification scores were assessed by computerized tomography for quantification of coronary artery calcification score and lateral lumbar radiography for aortic calcification score.

Results

This study group showed high prevalence of arterial calcification and 59% had verified CVD. Both CAC and AAC were significantly higher in patients with verified CVD. Only 22% had low turnover bone disease. There was a weak association between fluoride activity, which reflects bone turnover, measured in the lumbar spine, and CAC and between PTH and CAC. There was also a weak association between erosion surfaces and AAC. No significant association was found between calcification score and any other parameter measured.

Conclusions

The results in this study highlight the complexity, when evaluating the link between bone remodeling and vascular calcification in patients with multiple comorbidities and extensive atherosclerosis. Several studies suggest an impact of bone turnover on development of arterial calcification and there is some evidence of reduced progression of vascular calcification with improvement in bone status. The present study indicates an association between vascular calcification and bone turnover, even though many parameters of bone turnover failed to show significance. In the presence of multiple other factors contributing to the development of calcification, the impact of bone remodeling might be diminished.

Trial registration

The study is registered in ClinicalTrials.gov protocol registration and result system, ID is NCT02967042. Date of registration is 17/11/2016.

Coordinate roles for collagen VI and biglycan in regulating tendon collagen fibril structure and function

AUTHORS

Ryan J. Leiphart, Hai Phama, Tyler Harvey, Taishi Komori, Tina M. Kilts, Snehal S. Shetye, Stephanie N. Weiss, Sheila M. Adams, David E. Birk, Louis J. Soslowsky, Marian F. Young

ABSTRACT

Tendon is a vital musculoskeletal tissue that is prone to degeneration. Proper tendon maintenance requires complex interactions between extracellular matrix components that remain poorly understood. Collagen VI and biglycan are two matrix molecules that localize pericellularly within tendon and are critical regulators of tissue properties. While evidence suggests that collagen VI and biglycan interact within the tendon matrix, the relationship between the two molecules and its impact on tendon function remains unknown. We sought to elucidate potential coordinate roles of collagen VI and biglycan within tendon by defining tendon properties in knockout models of collagen VI, biglycan, or both molecules. We first demonstrated co-expression and co-localization of collagen VI and biglycan within the healing tendon, providing further evidence of cooperation between the two molecules during nascent tendon matrix formation. Deficiency in collagen VI and/or biglycan led to significant reductions in collagen fibril size and tendon mechanical properties. However, collagen VI-null tendons displayed larger reductions in fibril size and mechanics than seen in biglycan-null tendons. Interestingly, knockout of both molecules resulted in similar properties to collagen VI knockout alone. These results indicate distinct and non-additive roles for collagen VI and biglycan within tendon. This work provides better understanding of regulatory interactions between two critical tendon matrix molecules.

Short Cyclic Regimen with Parathyroid Hormone (PTH) Results in Prolonged Anabolic Effect Relative to Continuous Treatment Followed by Discontinuation in Ovariectomized Rats

AUTHORS

Wei-Ju Tseng, Wonsae Lee, Hongbo Zhao, Yang Liu, Wenzheng Wang, Chantal M. J. de Bakker, Yihan Li, Carlos Osuna, Wei Tong, Luqiang Wang, Xiaoyuan Ma, Ling Qin, X. Sherry Liu

ABSTRACT

Despite the potent effect of intermittent PTH treatment on promoting new bone formation, BMD rapidly decreases upon discontinuation of PTH administration. To uncover the mechanisms behind this adverse phenomenon, we investigated the immediate responses in bone microstructure and bone cell activities to PTH treatment withdrawal and the associated long-term consequences. Unexpectedly, intact female and estrogen-deficient female rats had distinct responses to the discontinuation of PTH treatment. Significant tibial bone loss and bone microarchitecture deterioration occurred in estrogen-deficient rats, with the treatment benefits of PTH completely lost 9 weeks after discontinuation. In contrast, no adverse effect was observed in intact rats, with sustained treatment benefit 9 weeks after discontinuation. Intriguingly, there is an extended anabolic period during the first week of treatment withdrawal in estrogen-deficient rats, during which no significant change occurred in the number of osteoclasts while the number of osteoblasts remained elevated compared to vehicle-treated rats. However, increases in number of osteoclasts and decreases in number of osteoblasts occurred 2 weeks after discontinuation of PTH treatment, leading to significant reduction in bone mass and bone microarchitecture. To leverage the extended anabolic period upon early withdrawal from PTH, a cyclic administration regimen with repeated cycles of on and off PTH treatment was explored. We demonstrated that the cyclic treatment regimen efficiently alleviated the PTH withdrawal-induced bone loss, improved bone mass, bone microarchitecture, and whole-bone mechanical properties, and extended the treatment duration.

In vivo imaging tools for functional assessment of biomaterials implanted bone regeneration

AUTHORS

Subhasis Roy; Prasenjit Mukherjee; Samit Kumar Nandi

ABSTRACT

Since the discovery of X-rays and its first use in imaging of a hand, bone tissue has been the chapter of interest in medical imaging. However, X-ray imaging poses limitations nowadays owing to the augmented complexity of implant scaffolds as well as with the advances in bone engineering. As a result, advanced follow-up imaging techniques are of paramount necessity for effective postoperative characterization. Moreover, it is also needed to search for non-invasive, high-sensitivity, and high-resolution structural, functional, and molecular imaging techniques such as acoustic, optical, magnetic, X-Ray, electron, ultrasound, and nuclear imaging, etc. as an alternative to normally used X-ray computed tomography. Further, enthusiastic preclinical scanners have turned out to be accessible, with sensitivity and resolution even superior to clinical scanners, as a consequence helping a rapid transformation from preclinical to clinical applications. Besides, recently, bone-specific probes and contrast agents are developing for better imaging tools in bone-tissue engineering applications. This review highlights such emerging preclinical imaging tools, each with its individual potencies and flaws, either used only or in combination. In particular, multimodal imaging will significantly add to improve the present understanding in the characterization of bone regenerative processes.