Applicants

Name   Dr. rer. nat. Zsuzsa Jenei-Lanzl, PhD (principal investigator)  

E-mail: zsuzsa.jenei-lanzl@friedrichsheim.de


Sympathetic influences on articular cartilage regeneration capacity and osteoarthritis manifestation


It is known that sympathetic nerve fibers are present in healthy and osteoarthritic synovium and that the sympathetic nervous system mediates numerous effects on adult skeletal system components. Furthermore, mechanical forces are critical for development and maintenance of normal cartilage structure. The existence of progenitor cells in healthy or osteoarthritic articular cartilage and their possible role in (osteoarthritis) OA manifestation has been confirmed. In recent chondrogenesis studies, we observed inhibition of chondrogenic extracellular matrix deposition and acceleration of chondrocyte hypertrophy after treatment with the sympathetic neurotransmitter norepinephrine (NE) at high concentrations under normoxic conditions. Additional experiments using adrenoceptor agonists and antagonists confirmed the involvement of b2-adrenoceptor. Our results suggest that NE may influence existing or migrating progenitor cells and play a role in the development and manifestation of OA. In this project, we will characterize NE-dependent b2-adrenoceptor-mediated signaling pathways responsible for effects on proliferation and chondrogenic differentiation of MSCs in detail with or without mechanical loading under normoxic and hypoxic conditions, because hypoxia reflects the physiological oxygen environment in cartilage tissue. Moreover, we will determine the effects of NE on OA manifestation and the involvement of b2-adrenoceptor in a murine experimental OA model. These experiments will allow new insight into the role of MSCs and sympathetic nerves in cartilage regeneration and OA development and might help to develop novel neuro-chondrogenic therapeutic options.



Key Achievements of the First Funding Period

Sympathetic nerve fibres producing NE are present in healthy and osteoarthritic synovium, and a subset of its adrenergic receptors (AR) are present (α1A-, α1B-, α2A-, α2B-, α2C and β2-AR) in all stem cell types and in chondrocytes [1]. MSC number is increased in human OA knee articular cartilage but the reason for this phenomenon is unknown. In the first funding period, we have investigated the effect of sympathetic neurotransmitter norepinephrine (NE) on the proliferation of trauma- and OA-BMSCs, and synovial adipose stem cells (sASC). We could show that NE in high but not in low concentrations or the β2-AR agonist formoterol inhibits the proliferation of both trauma- and OA BMCSs significantly in monolayer culture under physioxic conditions (Fig. 1). Interestingly, while sASC proliferation was not affected by any treatment (Fig. 1), NE enhanced sASCs migration (Fig. 2) and, at high concentrations, inhibited sASC chondrogenesis in pellet culture (Fig. 5 and Fig. 7) via α2-AR-mediated ERK1/2 phosphorylation. In conclusion, these results suggest that NE inhibits stem cell-dependent cartilage regeneration via modulating MSC proliferation, migration and chondrogenesis [2].

In vivo, together with SP4 and SP5 we have found that sympathectomy (Syx) attenuated cartilage degradation (Fig. 9) but aggravated OA-specific subchondral bone changes (Fig. 10) in mice with this experimental OA model and interestingly, DMM-induced OA resulted in elevated sympathetic tone (Fig. 11)(manuscript in preparation). These results demonstrated that that the sympathetic nervous system plays a crucial role in OA manifestation by exhibiting a dual cartilage-catabolic but bone-protective effect in a murine experimental OA model. Further experiments analyzing the sympathetic tone during OA progression have to be performed to understand the role of chronic sympathetic hyperactivity (chronic stress) in OA pathogenesis and for the development of novel therapeutic options targeting the SNS.

 

[1] Speichert S, Molotkov N, El Bagdadi K, Meurer A, Zaucke F, Jenei-Lanzl Z. Role of Norepinephrine in IL-1β-Induced Chondrocyte Dedifferentiation under Physioxia. Int J Mol Sci. 2019 Mar 11;20(5). pii: E1212. doi: 10.3390/ijms20051212.

[2] El Bagdadi K, Straub RH, Meurer A, Zaucke F, Jenei-Lanzl Z. Norepinephrine  inhibits chondrogenic differentiation of synovial adipose stem cells under physioxic conditions via α2AR- and β2AR-mediated ERK induction. Int J Mol Sci. 2019;20(13):3127. doi:10.3390/ijms20133127.

In vitro results

In vivo results