Disc degeneration primarily contributes to chronic low back and neck pain.Consequently,there is an urgent need to understand the spectrum of disc degeneration phenotypes such as fibrosis,ectopic calcification,herniati...Disc degeneration primarily contributes to chronic low back and neck pain.Consequently,there is an urgent need to understand the spectrum of disc degeneration phenotypes such as fibrosis,ectopic calcification,herniation,or mixed phenotypes.Amongst these phenotypes,disc calcification is the least studied.Ectopic calcification,by definition,is the pathological mineralization of soft tissues,widely studied in the context of conditions that afflict vasculature,skin,and cartilage.Clinically,disc calcification is associated with poor surgical outcomes and back pain refractory to conservative treatment.It is frequently seen as a consequence of disc aging and progressive degeneration but exhibits unique molecular and morphological characteristics:hypertrophic chondrocyte-like cell differentiation;TNAP,ENPP1,and ANK upregulation;cell death;altered Pi and PPi homeostasis;and local inflammation.Recent studies in mouse models have provided a better understanding of the mechanisms underlying this phenotype.It is essential to recognize that the presentation and nature of mineralization differ between AF,NP,and EP compartments.Moreover,the combination of anatomic location,genetics,and environmental stressors,such as aging or trauma,govern the predisposition to calcification.Lastly,the systemic regulation of calcium and Pi metabolism is less important than the local activity of PPi modulated by the ANK-ENPP1 axis,along with disc cell death and differentiation status.While there is limited understanding of this phenotype,understanding the molecular pathways governing local intervertebral disc calcification may lead to developing disease-modifying drugs and better clinical management of degeneration-related pathologies.展开更多
基金support by R01AR055655, R01AR074813, and R01AG073349 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute on Aging (NIA)supported by PXE International.
文摘Disc degeneration primarily contributes to chronic low back and neck pain.Consequently,there is an urgent need to understand the spectrum of disc degeneration phenotypes such as fibrosis,ectopic calcification,herniation,or mixed phenotypes.Amongst these phenotypes,disc calcification is the least studied.Ectopic calcification,by definition,is the pathological mineralization of soft tissues,widely studied in the context of conditions that afflict vasculature,skin,and cartilage.Clinically,disc calcification is associated with poor surgical outcomes and back pain refractory to conservative treatment.It is frequently seen as a consequence of disc aging and progressive degeneration but exhibits unique molecular and morphological characteristics:hypertrophic chondrocyte-like cell differentiation;TNAP,ENPP1,and ANK upregulation;cell death;altered Pi and PPi homeostasis;and local inflammation.Recent studies in mouse models have provided a better understanding of the mechanisms underlying this phenotype.It is essential to recognize that the presentation and nature of mineralization differ between AF,NP,and EP compartments.Moreover,the combination of anatomic location,genetics,and environmental stressors,such as aging or trauma,govern the predisposition to calcification.Lastly,the systemic regulation of calcium and Pi metabolism is less important than the local activity of PPi modulated by the ANK-ENPP1 axis,along with disc cell death and differentiation status.While there is limited understanding of this phenotype,understanding the molecular pathways governing local intervertebral disc calcification may lead to developing disease-modifying drugs and better clinical management of degeneration-related pathologies.
