Abstract
Pituitary adenylate cyclase activating polypeptide (PACAP) is an important neurotrophic factor influencing differentiation of neuronal elements and exerting protecting role during traumatic injuries or inflammatory processes of the central nervous system. Although increasing evidence is available on its presence and protecting function in various peripheral tissues, little is known about the role of PACAP in formation of skeletal components. To this end, we aimed to map elements of PACAP signalling in developing cartilage under physiological conditions and during oxidative stress. mRNAs of PACAP and its receptors (PAC1,VPAC1, VPAC2) were detectable during differentiation of chicken limb bud-derived chondrogenic cells in micromass cell cultures. Expression of PAC1 protein showed a peak on days of final commitment of chondrogenic cells. Administration of either the PAC1 receptor agonist PACAP 1-38, or PACAP 6-38 that is generally used as a PAC1 antagonist, augmented cartilage formation, stimulated cell proliferation and enhanced PAC1 and Sox9 protein expression. Both variants of PACAP elevated the protein expression and activity of the Ca-calmodulin dependent Ser/Thr protein phosphatase calcineurin. Application of PACAPs failed to rescue cartilage formation when the activity of calcineurin was pharmacologically inhibited with cyclosporine A. Moreover, exogenous PACAPs prevented diminishing of cartilage formation and decrease of calcineurin activity during oxidative stress. As an unexpected phenomenon, PACAP 6-38 elicited similar effects to those of PACAP 1-38, although to a different extent. On the basis of the above results, we propose calcineurin as a downstream target of PACAP signalling in differentiating chondrocytes either in normal or pathophysiological conditions. Our observations imply the therapeutical perspective that PACAP can be applied as a natural agent that may have protecting effect during joint inflammation and/or may promote cartilage regeneration during degenerative diseases of articular cartilage.
Highlights
Isolated from ovine hypothalamic extracts, pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the VIP–Secretin–GHRH–Glucagon superfamily [1]
As PACAP has a 100-fold higher binding affinity to the PAC1 receptor compared to VPAC receptors [21], we only investigated the protein expression of PAC1 in this study
The presence and functions of PACAP neuropeptides are broadly investigated in various peripheral tissues such as kidney, liver and testis, but little is known about its distribution in cartilage [9,46]
Summary
Isolated from ovine hypothalamic extracts, pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the VIP–Secretin–GHRH–Glucagon superfamily [1]. PACAP 1-38, the dominant form of the neuropeptide, is widely distributed in the central nervous system (CNS) and is present in several peripheral tissues such as gonads [2], intestinal system [3], urinary tract [4], as well as in fluid compartments including blood plasma [5] and human milk [6]. PACAP is regarded as a neurotrophic [14,15] and anti-inflammatory substance in the CNS [16] and is reported to prevent harmful effects of oxidative stress in various tissues [17,18,19]
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