Senescence induces proteolytically-active PAPP-A secretion and association with extracellular vesicles in human pre-adipocytes

Cheryl A. Conover, Laurie K. Bale

Research output: Contribution to journalArticlepeer-review

Abstract

Senescence is a cellular response to various stressors characterized by irreversible cell cycle arrest, resistance to apoptosis and expression of a senescence-associated secretory phenotype (SASP). Interestingly, studies where senescent cells were deleted in mice produced beneficial effects similar to those where the zinc metalloproteinase, PAPP-A, was deleted in mice. In this study, we investigated the effect of senescence on PAPP-A secretion and activity in primary cultures of adult human pre-adipocytes. Cultured pre-adipocytes were isolated from subcutaneous (Sub) and omental (Om) fat. Senescence was induced with low dose etoposide. PAPP-A protein was measured by an ultrasensitive PAPP-A ELISA. PAPP-A proteolytic activity was measured by a specific substrate cleavage assay. Senescence significantly increased PAPP-A levels in both Sub and Om conditioned medium (CM) 8- to 15-fold over non-senescent CM. Proteolytic activity reflected PAPP-A protein with 12- to 18-fold greater activity in senescent CM versus non-senescent CM. Furthermore, PAPP-A was found at high levels on the surface of extracellular vesicles secreted by senescent pre-adipocytes and was proteolytically active. In conclusion, we identified enzymatically active PAPP-A as a component of human pre-adipocyte SASP. This recognition warrants further investigation of PAPP-A as a new biomarker for senescence and a potential therapeutic target to control of the spread of senescence in adipose tissue.

Original languageEnglish (US)
Article number112070
JournalExperimental Gerontology
Volume172
DOIs
StatePublished - Feb 2023

Keywords

  • Extracellular vesicles
  • Human pre-adipocytes
  • PAPP-A
  • Protease
  • Senescence

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Cell Biology

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