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Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1

K M Lawrence1, R C Jones2, T R Jackson2

  • 1Division of Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, The University of Manchester, Wilmslow Road, Manchester, M20 4GJ, UK. kevin.lawrence@manchester.ac.uk.

Scientific Reports
|July 13, 2017
PubMed

Insights

Urocortin1 (Ucn1) protects human chondrocytes from osteoarthritis (OA) by inhibiting the Piezo1 channel. This novel pathway involves cyclic adenosine monophosphate (cAMP) and phospholipase A2 (PLA2), offering potential OA intervention strategies.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Physiology

Background:

  • Osteoarthritis (OA) involves articular cartilage destruction and chondrocyte death.
  • The role of endogenous peptides in chondrocyte survival is not fully understood.

Purpose of the Study:

  • To investigate the role of urocortin1 (Ucn1) and its receptors in human articular chondrocytes (AC).
  • To elucidate the signaling pathways involved in Ucn1-mediated chondrocyte survival and cell death.

Main Methods:

  • Primary human articular chondrocytes (AC) were used.
  • Expression of Ucn1, CRF-R1, and CRF-R2 was analyzed.
  • Selective antagonists (CP-154526) and blockers (Gadolinium) were employed.
  • Intracellular calcium (Ca2+) levels, p53 expression, and caspase activity were measured.
  • Mechanosensitive channel Piezo1 and cAMP/PLA2 pathways were investigated.

Main Results:

  • Ucn1 acts as an autocrine/paracrine pro-survival factor in AC, primarily through CRF-R1.
  • Antagonism of CRF-R1 led to chondrocyte cell death, increased intracellular Ca2+, and activation of p53 and caspases.
  • Ucn1 inhibits the Piezo1 channel, preventing Ca2+ influx and cell death.
  • Ucn1's inhibitory effect on Piezo1 is mediated by increased cAMP and subsequent PLA2 inactivation.

Conclusions:

  • Urocortin1 (Ucn1) is a crucial pro-survival factor for human articular chondrocytes (AC).
  • Ucn1 protects AC by inhibiting the mechanosensitive Piezo1 channel via a cAMP/PLA2-dependent mechanism.
  • These findings reveal novel pathways in OA pathogenesis and suggest potential therapeutic targets for OA intervention.

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