Abstract
Pituitary adenylate cyclase activating polypeptide (PACAP) is an evolutionarly conserved neuropeptide which is produced by various neuronal and non-neuronal cells, including cartilage and bone cells. PACAP has trophic functions in tissue development, and it also plays a role in cellular and tissue aging. PACAP takes part in the regulation of chondrogenesis, which prevents insufficient cartilage formation caused by oxidative and mechanical stress. PACAP knockout (KO) mice have been shown to display early aging signs affecting several organs. In the present work, we investigated articular cartilage of knee joints in young and aged wild-type (WT) and PACAP KO mice. A significant increase in the thickness of articular cartilage was detected in aged PACAP gene–deficient mice. Amongst PACAP receptors, dominantly PAC1 receptor was expressed in WT knee joints and a remarkable decrease was found in aged PACAP KO mice. Expression of PKA-regulated transcription factors, Sox5, Sox9 and CREB, decreased both in young and aged gene deficient mice, while Sox6, collagen type II and aggrecan expressions were elevated in young but were reduced in aged PACAP KO animals. Increased expression of hyaluronan (HA) synthases and HA-binding proteins was detected parallel with an elevated presence of HA in aged PACAP KO mice. Expression of bone related collagens (I and X) was augmented in young and aged animals. These results suggest that loss of PACAP signaling results in dysregulation of cartilage matrix composition and may transform articular cartilage in a way that it becomes more prone to degenerate.
Highlights
Articular cartilage is a unique type of connective tissue in the skeletal system with very poor regenerative capacity
dimethylmethylene blue (DMMB) staining was performed to demonstrate the presence of metachromatic extracellular matrix (ECM) components (PGs, sulphated GAGs)
We investigated the expression of collagen type I and X which appears in bony calcified structures. mRNA and protein expressions of collagen type I increased in young Pituitary adenylate cyclase activating polypeptide (PACAP) KO cartilage, and even stronger elevation was detected in aged PACAP KO joints (Fig. 6a, b)
Summary
Articular cartilage is a unique type of connective tissue in the skeletal system with very poor regenerative capacity Major factors behind this phenomenon are its avascular, aneural nature and the postmitotic character of adult chondrocytes. In the deep layers of articular cartilage (hypertrophic zone and calcification zone), ECM becomes calcified providing a tissue with intermediate biomechanical properties interconnecting articular cartilage and subchondral bone. In this region, chondrocytes are terminally differentiated hypertrophic cells which subsequently undergo apoptosis and the whole tissue serves as a template for trabecular bone formation (Zevenbergen et al 2018). In pathological conditions, such as inflammation, oxidative stress or increased mechanical force, the composition of cartilage-specific ECM can be disintegrated and cartilage degeneration may occur (Poulet and Staines 2016)
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