Artikel
Sympathicus as a double-edged sword in osteoarthritis development: norepinephrine aggravates cartilage degeneration but attenuates subchondral bone changes
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Veröffentlicht: | 22. Oktober 2019 |
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Gliederung
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Objectives: Osteoarthritis (OA) is a degenerative joint disease and involves the interaction of cartilage and surrounding tissues, which are innervated by sympathetic nerve fibers. Moreover, the most important sympathetic neurotransmitter norepinephrine (NE) was detected in the synovial fluid of trauma and OA patients. The objective of this study was to analyze how the sympathicus and especially NE influence the synovial stem cell-dependent cartilage regeneration in vitro and the OA development in vivo.
Methods: Synovial adipose-derived stem cells (sASCs) were isolated from OA patients undergoing knee replacement surgery. After detection of different adrenergic receptor (AR) subtypes, proliferation and chondrogenic differentiation of sASCs were evaluated in the presence of NE (10-9-10-6 M) or α- and β-AR antagonists under physioxia (2% O2). After 21 days of chondrogenesis, the expression of chondrogenic and hypertrophic markers as well as key signaling pathways (ERK, PKA) were analyzed. Experimental OA was induced in C57BL/6 wildtype mice (WT) and in sympathectomized mice (Syx) by destabilization of the medial meniscus (DMM). OA progression was evaluated by histological scoring (OARSI score), micro- and nano-CT and measurement of serum CTX-II.
Results and conclusion: sASCs in pellet culture expressed α1B-, α2A-, α2B-, α2C-, and β2-AR. NE treatment did not affect proliferation. However, pellet volume, glycosaminoglycan and type II collagen content decreased significantly after incubation with high-dose NE. These effects were mediated by ERK phosphorylation and completely reversed by the α2-AR antagonist. After DMM, Syx resulted in less pronounced cartilage degradation and a significant decrease of CTX-II compared to WT. At the same time, bone volume, thickness of the subchondral bone plate, and calcified cartilage volume of the medial condyle increased in Syx.
NE inhibits the chondrogenic differentiation of sASC by activating ERK signaling via α2-AR. Syx attenuated cartilage degradation but aggravated OA-specific subchondral bone changes. Sympathicus plays a crucial role in OA pathogenesis but has opposing effects in different tissues involved. A tissue-specific modulation of adrenergic signaling pathways represents a promising approach for the development of novel OA therapies.