Report From the 6th International Meeting on Bone Marrow Adiposity (BMA2020)

AUTHORS

Erica L. Scheller, Meghan E. McGee-Lawrence, and Beata Lecka-Czernik

ABSTRACT

The 6th International Meeting on Bone Marrow Adiposity (BMA) entitled “Marrow Adiposity: Bone, Aging, and Beyond” (BMA2020) was held virtually on September 9th and 10th, 2020. The mission of this meeting was to facilitate communication and collaboration among scientists from around the world who are interested in different aspects of bone marrow adiposity in health and disease. The BMA2020 meeting brought together 198 attendees from diverse research and clinical backgrounds spanning fields including bone biology, endocrinology, stem cell biology, metabolism, oncology, aging, and hematopoiesis. The congress featured an invited keynote address by Ormond MacDougald and ten invited speakers, in addition to 20 short talks, 35 posters, and several training and networking sessions. This report summarizes and highlights the scientific content of the meeting and the progress of the working groups of the BMA society (http://bma-society.org/).

A glucuronated flavone TMMG spatially targets chondrocytes to alleviate cartilage degeneration through negative regulation of IL-1β

AUTHORS

Priyanka Kothari, Geeta Dhaniya, Anirban Sardar, Shradha Sinha, Aboli Girme, Divya Rai, Kunal Chutani, Lal Hingorani, Ritu Trivedi

ABSTRACT

Chondrocytes are the only resident cell types that form the extracellular matrix of cartilage. Inflammation alters the anabolic and catabolic regulation of chondrocytes, resulting in the progression of osteoarthritis (OA). The potential of TMMG, a glucuronated flavone, was explored against the pathophysiology of OA in both in vitro and in vivo models. The effects of TMMG were evaluated on chondrocytes and the ATDC5 cell line treated with IL-1β in an established in vitro inflammatory OA model. An anterior cruciate ligament transection (ACLT) model was used to simulate post-traumatic injury in vivo. Micro-CT and histological examination were employed to examine the micro-architectural status and cartilage alteration. Further, serum biomarkers were measured using ELISA to assess OA progression. In-vitro, TMMG reduced excessive ROS generation and inhibited pro-inflammatory IL-1β secretion by mouse chondrocytes and macrophages, which contributes to OA progression. This expression pattern closely mirrored osteoclastogenesis prevention. In-vivo results show that TMMG prevented chondrocyte apoptosis and degradation of articular cartilage thickness, subchondral parameters, and elevated serum COMP, CTX-II, and IL-1β which were significantly restored in 5 and 10 mg.kg−1day−1 treated animals and comparable to the positive control Indomethacin. In addition, TMMG also improved cartilage integrity and decreased the OARSI score by maintaining chondrocyte numbers and delaying ECM degradation. These findings suggest that TMMG may be a prospective disease-modifying agent that can mitigate OA progression.

Aging and the carotid body: A scoping review

AUTHORS

Camillo Di Giulio, Susi Zara, Andrea Mazzatenta, Vittore Verratti, Andrea Porzionato, Amelia Cataldi, Mieczyslaw Pokorski

ABSTRACT

The carotid body (CB) is a neuroepithelial tissue consisting of O2-sensitive glomus cells that constantly scan the arterial blood for O2 and generate a discharge as an inverse function of O2 content. Aging is a cumulative result of decreased O2 supply paralleled by a decreased O2 tissue demand and oxidative damage to cells derived from aerobic metabolism. Here we studied how CB affects the aging process. This is a study of CB ultrastructural morphometry and immunohistochemical expression of proteins underlying CB responsiveness. The study was based on human CBs obtained from cadavers of people who died due to traumatic events in young and old age. The study was supplemented by investigations of CBs obtained from young and old rats subjected to chronic normoxic and hypoxic conditions. We found changes in the old normoxic CBs akin to the effects of chronic hypoxia such as enhanced extracellular matrix, reduced synaptic contacts between glomus cells, fewer glomus cells, secretory vesicles, and mitochondria. These changes were accompanied by enhanced expressions of hypoxia-inducible factor one-alpha (HIF-1α), vascular endothelial growth factor (VEGF), and nitric oxide synthase (NOS2). We conclude that hypoxia and aging share a common background consisting of deficient O2 tissue supply, mitochondrial dysfunction, and a limited ability to deal with increased cellular oxidative stress. Aging leads to adaptative reductions in CB responsiveness to hypoxia shifting the chemosensory setpoint upward. We submit that the attenuated CB sensitivity at old age may be tantamount to “physiological denervation” leading to a gradual loss of the chemosensing role in the prevention of tissue hypoxia by increasing lung ventilation.

A prognostic model of clear cell renal cell carcinoma based on telomere-related lncRNAs

AUTHORS

Hao Chen, Li Li, Longkun Mao, Jianfeng Zeng

ABSTRACT

Background

Telomeres have been demonstrated to be critical in the development of multiple tumors. However, the association of telomere-related lncRNAs with clear cell renal cell carcinoma (ccRCC) and their prognostic roles in ccRCC patients remain unknown.

METHODS

Expression matrix and clinicopathological data of ccRCC patients were extracted from The Cancer Genome Altas and UCSC Xena browser. The differentially expressed genes were identified and intersected with the telomere-related genes downloaded from the Telnet database. Telomere-related lncRNAs were screened by the univariate Cox regression analysis. Each patient's risk score was calculated to establish a nomogram based on eight telomere-related lncRNAs screened by the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analysis. The correlation between telomere-related lncRNAs and immune cells was assessed by the CIBEERSORT algorithm. The immune and stromal infiltrations were quantified by the ESTIMATE algorithm. Gene set enrichment analysis (GSEA) was performed to explore the selected lncRNA functions.

Result

We screened eight telomere-related lncRNAs and established a risk score model for predicting survival in ccRCC patients. A nomogram was developed to predict the survival outcomes of postoperative patients by integrating several clinical factors, and a well-predictive effect was observed. The correlation between selected lncRNAs and immune function was explored by the CIBEERSORT and ESTIMATE algorithms. Besides, GSEA showed that telomere-related lncRNAs could affect ccRCC prognosis through multiple pathways.

Metabolism and Disposition of the Novel Oral Factor XIa Inhibitor Asundexian in Rats and in Humans

AUTHORS

Isabel Piel, Anna Engelen, Dieter Lang, Simone I. Schulz, Michael Gerisch, Christine Brase, Wiebke Janssen, Lukas Fiebig, Stefan Heitmeier & Friederike Kanefendt

ABSTRACT

Background and Objectives

Current anticoagulants pose an increased risk of bleeding. The development of drugs targeting factor XIa, like asundexian, may provide a safer treatment option. A human mass‑balance study was conducted to gain a deeper understanding of the absorption, distribution, metabolism, excretion, and potential for drug–drug interaction of asundexian. Additionally, an overview of the biotransformation and clearance pathways for asundexian in humans and bile-duct cannulated (BDC) rats in vivo, as well as in vitro in hepatocytes of both species, is reported.

Methods

The mass balance, biotransformation, and excretion pathways of asundexian were investigated in six healthy volunteers (single oral dose of 25 mg [14C]asundexian) and in BDC rats (intravenous [14C]asundexian 1 mg/kg).

Results

Overall recovery of radioactivity was 101% for humans (samples collected up to 14 days after dosing), and 97.9% for BDC rats (samples collected in the 24 h after dosing). Radioactivity was mainly excreted into feces in humans (80.3%) and into bile/feces in BDC rats (> 94%). The predominant clearance pathways in humans were amide hydrolysis to metabolite M1 (47%) and non-labeled M9 with subsequent N-acetylation to M10; oxidative biotransformation was a minor pathway (13%). In rats, hydrolysis of the terminal amide to M2 was the predominant pathway. In human plasma, asundexian accounted for 61.0% of total drug-related area under the plasma concentration–time curve (AUC); M10 was the major metabolite (16.4% of the total drug-related AUC). Excretion of unmetabolized drug was a significant clearance pathway in both species (human, ~ 37%; BDC rat, ~ 24%). The near-complete bioavailability of asundexian suggests negligible limitations on absorption and first-pass metabolism. Comparison with radiochromatograms from incubations with human or rat hepatocytes indicated consistency across species and a good overall in vitro/in vivo correlation.

Conclusions

Similar to preclinical experiments, total asundexian-derived radioactivity is cleared quantitatively predominantly via feces. Excretion occurs mainly via amide hydrolysis and as the unchanged drug.

Blocking CCN2 Reduces Established Bone Loss Induced by Prolonged Intense Loading by Increasing Osteoblast Activity in Rats

AUTHORS

Alex G Lambi, Michele Y Harris, Mamta Amin, Patrice G Joiner, Brendan A Hilliard, Soroush Assari, Steven N Popoff, Mary F Barbe

ABSTRACT

We have an operant model of reaching and grasping in which detrimental bone remodeling is observed rather than beneficial adaptation when rats perform a high-repetition, high-force (HRHF) task long term. Here, adult female Sprague–Dawley rats performed an intense HRHF task for 18 weeks, which we have shown induces radial trabecular bone osteopenia. One cohort was euthanized at this point (to assay the bone changes post task; HRHF-Untreated). Two other cohorts were placed on 6 weeks of rest while being simultaneously treated with either an anti-CCN2 (FG-3019, 40 mg/kg body weight, ip; twice per week; HRHF-Rest/anti-CCN2), or a control IgG (HRHF-Rest/IgG), with the purpose of determining which might improve the trabecular bone decline. Results were compared with food-restricted control rats (FRC). MicroCT analysis of distal metaphysis of radii showed decreased trabecular bone volume fraction (BV/TV) and thickness in HRHF-Untreated rats compared with FRCs; responses improved with HRHF-Rest/anti-CCN2. Rest/IgG also improved trabecular thickness but not BV/TV. Histomorphometry showed that rest with either treatment improved osteoid volume and task-induced increases in osteoclasts. Only the HRHF-Rest/anti-CCN2 treatment improved osteoblast numbers, osteoid width, mineralization, and bone formation rate compared with HRHF-Untreated rats (as well as the latter three attributes compared with HRHF-Rest/IgG rats). Serum ELISA results were in support, showing increased osteocalcin and decreased CTX-1 in HRHF-Rest/anti-CCN2 rats compared with both HRHF-Untreated and HRHF-Rest/IgG rats. These results are highly encouraging for use of anti-CCN2 for therapeutic treatment of bone loss, such as that induced by chronic overuse. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.