Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1

Abstract

Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstrate its role as an autocrine/paracrine pro-survival factor. This effect could only be removed using the CRF-R1 selective antagonist CP-154526, suggesting Ucn1 acts through CRF-R1 when promoting chondrocyte survival. This cell death was characterised by an increase in p53 expression, and cleavage of caspase 9 and 3. Antagonism of CRF-R1 with CP-154526 caused an accumulation of intracellular calcium (Ca2+) over time and cell death. These effects could be prevented with the non-selective cation channel blocker Gadolinium (Gd3+). Therefore, opening of a non-selective cation channel causes cell death and Ucn1 maintains this channel in a closed conformation. This channel was identified to be the mechanosensitive channel Piezo1. We go on to determine that this channel inhibition by Ucn1 is mediated initially by an increase in cyclic adenosine monophosphate (cAMP) and a subsequent inactivation of phospholipase A2 (PLA2), whose metabolites are known to modulate ion channels. Knowledge of these novel pathways may present opportunities for interventions that could abrogate the progression of OA.

PIEZO1 functions as a potential oncogene by promoting cell proliferation and migration in gastric carcinogenesis

“…This type of channel directly senses mechanical force and converts environmental signals into intracellular Ca 2+ responses . Properties of PIEZO proteins were soon illustrated in different of eukaryotic cell processes . Both PIEZO family members share physiological and biological similarities.…”

“…7 Properties of PIEZO proteins were soon illustrated in different of eukaryotic cell processes. [7][8][9][10][11][12] Both PIEZO family members share physiological and biological similarities. However, their expression patterns are varies in tissues.…”

Mechanoelectrical transduction in chondrocytes

“…More recently, the PIEZO1‐mediated accumulation of intracellular Ca 2+ in response to compressive loading has been implicated in apoptotic cell death in chondrocytes, potentially contributing to the development of OA in some individuals. This observation is supported by an additional study showing that the peptide, urocortin, can protect chondrocytes from apoptosis by blocking PIEZO1 …”

“…This observation is supported by an additional study showing that the peptide, urocortin, can protect chondrocytes from apoptosis by blocking PIEZO1. 16…”

Discovery of Selenocysteine as a Potential Nanomedicine Promotes Cartilage Regeneration With Enhanced Immune Response by Text Mining and Biomedical Databases

“…It also lacks chondrocytes, and has relatively low sculpting capacity (Cheng et al, 2019). The chondrocytes in the matrix pits have low metabolic activity (Lawrence et al, 2017). They mainly obtain necessary nutrients and excrete metabolites through penetration.…”