Effects of suppressing bioavailability of insulin-like growth factor on age-associated intervertebral disc degeneration

Rebecca Kritschil, Zhongying Zhang, Changbin Lei, Jiongbiao Zhong, Qing Dong, Joon Lee, Cheryl A. Conover, Gwendolyn Sowa, Abbe N. Vallejo, Nam Vo

Research output: Contribution to journalArticlepeer-review

Abstract

Suppression of the insulin-like growth factor-1 (IGF-1) signaling pathway reduces age-related disorders and increases lifespan across species, making the IGF-1 pathway a key regulator of aging. Previous in vitro intervertebral disc cell studies have reported the pro-anabolic effect of exogenously adding IGF-1 on matrix production. However, the overall effects of suppressing IGF-1 signaling on age-related intervertebral disc degeneration (IDD) is not known. Here, the effects of suppressing IGF-1 signaling on age-related IDD in vivo were examined using PAPPA−/− mice. These are animals with targeted deletion of pregnancy-associated plasma protein A (PAPPA), the major protease that cleaves inhibitory IGF binding proteins that control bioavailability of IGF-1 for cell signaling. Compared to age-matched wild-type (Wt) littermates, reduced levels of matrix proteoglycan (PG) and aggrecan were seen in discs of 23-month old PAPPA−/− mice. Decreased aggrecanolysis and expression of two key catabolic markers, matrix metalloproteinase-3 and a disintegrin and metalloproteinase with thrombospondin motifs-4, were also observed in discs of old PAPPA−/− mice compared to Wt littermates. Suppressing IGF-1 signaling has been implicated to shift cellular metabolism toward maintenance rather than growth and decreasing cellular senescence. Along this line, discs of old PAPPA−/− mice also exhibited lower cellular senescence, assessed by p53 and lamin B1 markers. Collectively, the data reveal complex regulation of disc matrix homeostasis by PAPPA/IGF-1 signaling during chronologic aging, that is, reduced IGF-1 bioavailability confers the benefit of decreasing disc cellular senescence and matrix catabolism but also the disadvantage of decreasing disc PG matrix anabolism. This pathway requires further mechanistic elucidation before IGF-1 could be considered as a therapeutic growth factor for treating IDD.

Original languageEnglish (US)
Article numbere1112
JournalJOR Spine
Volume3
Issue number4
DOIs
StatePublished - Dec 2020

Keywords

  • aging
  • cellular senescence
  • IGF-1
  • intervertebral disc degeneration
  • PAPPA
  • proteoglycan

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

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