Abstract
Intervertebral disc (IVD), a moderately moving joint located between the vertebrae, has a limited capacity for self-repair, and treating injured intervertebral discs remains a major challenge. The development of innovative therapies to reverse IVD degeneration relies primarily on the discovery of key molecules that, occupying critical points of regulatory mechanisms, can be proposed as potential intradiscal injectable biological agents. This study aimed to elucidate the underlying mechanism of the reciprocal regulation of two genes differently involved in IVD homeostasis, the miR-221 microRNA and the TRPS1 transcription factor. Human lumbar IVD tissue samples and IVD primary cells were used to specifically evaluate gene expression and perform functional analysis including the luciferase gene reporter assay, chromatin immunoprecipitation, cell transfection with hTRPS1 overexpression vector and antagomiR-221. A high-level expression of TRPS1 was significantly associated with a lower pathological stage, and TRPS1 overexpression strongly decreased miR-221 expression, while increasing the chondrogenic phenotype and markers of antioxidant defense and stemness. Additionally, TRPS1 was able to repress miR-221 expression by associating with its promoter and miR-221 negatively control TRPS1 expression by targeting the TRPS1-3′UTR gene. As a whole, these results suggest that, in IVD cells, a double-negative feedback loop between a potent chondrogenic differentiation suppressor (miR-221) and a regulator of axial skeleton development (TRPS1) exists. Our hypothesis is that the hostile degenerated IVD microenvironment may be counteracted by regenerative/reparative strategies aimed at maintaining or stimulating high levels of TRPS1 expression through inhibition of one of its negative regulators such as miR-221.
Highlights
Intervertebral disc (IVD) degeneration can occur in any area of the spine for different reasons including trauma, chronic overload, aging or genetic factors
Degenerated discs, classified according to Pfirrmann grading system, expressed low levels of TRPS1, on the contrary a high-level expression of TRPS1 was significantly associated with the lower pathological stage
Research on gene expression modulation during both physiological and disease processes of IVD is focusing on attributing critical roles to transcription factors and non-coding RNAs, for what concerns their impact in diverse target genes, and their interplay [32,33]
Summary
Intervertebral disc (IVD) degeneration can occur in any area of the spine (cervical, thoracic and lumbar) for different reasons including trauma, chronic overload, aging or genetic factors. It represents a major cause of lower back pain, a leading cause of disability worldwide [1]. Degenerated discs have a hypoxic and inflammatory microenvironment. Cells 2019, 8, 1170 leading to up-regulation of catabolic factors and further degeneration [4]. This microenvironment is tricky to understand from a biochemical point of view due to its great heterogeneity. Detecting potential specific therapeutic target molecules is not easy and remains a major challenge
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
