Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility

Michaela Tencerova,Morten Frost,Florence Figeac,Tina Kamilla Nielsen,Dalia Ali,Jens-Jacob Lindegaard Lauterlein,Thomas Levin Andersen,Anders Kristian Haakonsson,Alexander Rauch,Jonna Skov Madsen,Charlotte Ejersted,Kurt Højlund,Moustapha Kassem

doi:10.1016/j.celrep.2019.04.066

Abstract

Obesity is associated with increased risk for fragility fractures. However, the cellular mechanisms are unknown. Using a translational approach combining RNA sequencing and cellular analyses, we investigated bone marrow stromal stem cells (BM-MSCs) of 54 men divided into lean, overweight, and obese groups on the basis of BMI. Compared with BM-MSCs obtained from lean, obese BM-MSCs exhibited a shift of molecular phenotype toward committed adipocytic progenitors and increased expression of metabolic genes involved in glycolytic and oxidoreductase activity. Interestingly, compared with paired samples of peripheral adipose tissue-derived stromal cells (AT-MSCs), insulin signaling of obese BM-MSCs was enhanced and accompanied by increased abundance of insulin receptor positive (IR+) and leptin receptor positive (LEPR+) cells in BM-MSC cultures. Their hyper-activated metabolic state was accompanied by an accelerated senescence phenotype. Our data provide a plausible explanation for the bone fragility in obesity caused by enhanced insulin signaling leading to accelerated metabolic senescence of BM-MSCs.

Highlights

Obesity is a major health problem worldwide, and besides metabolic complications such as insulin resistance, type 2 diabetes (T2D), and liver steatosis, bone fragility is increasingly recognized (Napoli et al, 2017)
Obesity is associated with increased bone marrow adipose tissue (BMAT) that alters bone marrow (BM) composition and may change bone architecture and bone material properties that contribute to reduced bone quality (Ambrosi et al, 2017; Boskey and Imbert, 2017; Naveiras et al, 2009; Rubin et al, 2007)
Obesity-Associated Increase in Bone Mass Is Accompanied by Low Bone Turnover To investigate whether obesity affects the cellular and molecular phenotype of BM-MSCs, we enrolled 54 healthy men subdivided into groups of lean, overweight (OW), and obese on the basis of BMI

Summary

Introduction

Obesity is a major health problem worldwide, and besides metabolic complications such as insulin resistance, type 2 diabetes (T2D), and liver steatosis, bone fragility is increasingly recognized (Napoli et al, 2017). Recent epidemiological studies have reported an association between obesity and increased risk for fragility fractures at several anatomical sites (Gonnelli et al, 2014). The differentiation potential of BM-MSCs is tightly regulated via several factors present in the BM microenvironment, including secreted proteins and hormones (Tencerova and Kassem, 2016) Some of these factors (e.g., secreted frizzled-related protein [sFRP-1] and legumain [LGMN]) determine the commitment of BM-MSCs into the adipocyte or osteoblast lineages (Abdallah and Kassem, 2012; Jafari et al, 2017). Under steady-state conditions, there is a balance between BM-MSCs and their committed progenitors This balance alters with aging and osteoporosis because of microenvironmental changes (Kassem and Marie, 2011)

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