Cross platform analysis of transcriptomic data identifies ageing has distinct and opposite effects on tendon in males and females

Abstract

The development of tendinopathy is influenced by a variety of factors including age, gender, sex hormones and diabetes status. Cross platform comparative analysis of transcriptomic data elucidated the connections between these entities in the context of ageing. Tissue-engineered tendons differentiated from bone marrow derived mesenchymal stem cells from young (20–24 years) and old (54–70 years) donors were assayed using ribonucleic acid sequencing (RNA-seq). Extension of the experiment to microarray and RNA-seq data from tendon identified gender specific gene expression changes highlighting disparity with existing literature and published pathways. Separation of RNA-seq data by sex revealed underlying negative binomial distributions which increased statistical power. Sex specific de novo transcriptome assemblies generated fewer larger transcripts that contained miRNAs, lincRNAs and snoRNAs. The results identify that in old males decreased expression of CRABP2 leads to cell proliferation, whereas in old females it leads to cellular senescence. In conjunction with existing literature the results explain gender disparity in the development and types of degenerative diseases as well as highlighting a wide range of considerations for the analysis of transcriptomic data. Wider implications are that degenerative diseases may need to be treated differently in males and females because alternative mechanisms may be involved.

Spectrum of Tendon Pathologies: Triggers, Trails and End-State

“…A follow up study of the microarray data by Popov et al has shown that several members of the ephrin receptor family, important for cell-cell signaling, are significantly downregulated in aged/degenerative cells but interestingly, reconstituted some cellular features such as self-renewability and wound healing potential are greatly improved. Cross platform analysis of transcriptomic data investigated connections between age, gender and sex hormones during the development of tendinopathy and identified that in old males decreased expression of CRABP2 leads to cell proliferation, whereas in old females it leads to cellular senescence [32]. This study gives the important notion that tendon degenerative diseases may need to be treated differently in males and females because alternative mechanisms may be involved [32].…”

“…Cross platform analysis of transcriptomic data investigated connections between age, gender and sex hormones during the development of tendinopathy and identified that in old males decreased expression of CRABP2 leads to cell proliferation, whereas in old females it leads to cellular senescence [32]. This study gives the important notion that tendon degenerative diseases may need to be treated differently in males and females because alternative mechanisms may be involved [32]. Moreover, a number of studies based on RNA sequencing were recently released, revealing higher cellular heterogeneity in tendon tissues than ever expected.…”

Epigenetic mechanisms in Tendon Ageing

“…Given the wide inter- and intra-species variation in tendon structure and function, as well as between sex variance in tendon homeostasis, 17 further work is required to investigate the influencers of normal ageing in tendon. This is particularly true in relation to the non-coding RNAs as this is a rapidly expanding area and one which is still poorly understood.…”

“… 15 A transcriptomic meta-analysis study of both tendon and tissue-engineered tendon constructs demonstrated distinct differences in how ageing affects males and females. 17 As the incidence and anatomical location of tendinopathy is known to be influenced by sex, 18 this difference in normal sex-related ageing may be pivotal in understanding the predisposition to, and therefore ability to prevent disease.…”

“…The effect of ageing on tendon tissue has been investigated in rats, 20 mice, 21 horses 4 , 9 , 11 and humans. 17 , 22 , 23 Whilst animal models using mice and rats remain important to delineate the relationship between contributory factors to tendinopathy, these models have limitations. Rodent models lack the comparable longevity, size to mass ratio as well as the onset of the multifaceted degenerative changes known to contribute human tendon pathology.…”