will take place on Tuesday, November 19th, 2024 from 16:00 to 17:00 hours in CBBM Building, Ground Floor, Seminar Room Levi-Montalcini.
Host: Prof. Henrik Oster
Institute of Neurobiology
Abstract: To Biological rhythms play a crucial role in the development of various musculoskeletal disorders. Bone, cartilage and tendons have peripheral oscillators with independent and self-sustaining timing systems that can interact with and influence biological phenomena like oxidative stress, inflammatory responses, and cellular growth and differentiation. This interaction is vital in the onset and progression of degeneration phenomenon.
Our previous research has demonstrated that the rhythm of the Achilles tendon clock was disrupted during the development of Achilles tendinopathy (AT), as indicated by the decreased amplitude of Bmal1 and Nrf2 rhythm expression. Mechanistically, the knockdown of Bmal1 disrupted the Achilles tendon clock, thereby destroying the Bmal1-Nrf2 axis dependent molecular defense mechanism, and exacerbating the inflammatory response, whereas overexpression of Bmal1 had a protective effect. Furthermore, a significant increase in inflammatory mediators occurs before fibrotic pathological changes in tendinopathy, with IL-1 shown to disrupt the Achilles tendon circadian rhythm through the Dbp-PPARγ axis both in vivo and in vitro. Disruption of the circadian rhythm by a nocturnal disturbance model significantly exacerbates AT. Overall, our study highlights the potential of targeting the Achilles tendon circadian clock as a promising therapeutic strategy for AT.
Additionally, our ongoing project has found that changes in feeding habits lead to alterations in the intestinal circadian rhythm. Mice fed exclusively during the light phase (daytime feeding or inverted feeding, DF) exhibit a phase inversion of the intestinal circadian rhythm compared to those fed at night or ad libitum, and also display osteoporotic phenotypes. We will further investigate using Bmal1-iKO (intestine-specific knockout of Bmal1) and Nr1d1-iKO mice.
Clinically, we have observed that patients undergoing joint replacement in the morning have a significantly higher postoperative thrombosis rate compared to those in the afternoon, and the expression of coagulation factor X (FX) is also higher in the morning. We have also found that the expression of FX in mice exhibits rhythmicity, which appears to be associated with the rhythmic expression of Bmal1 and Nr1d1. In a mouse model of inferior vena cava thrombosis, modeling at the peak of coagulation factor X rhythmic expression (ZT4) results in more severe thrombosis than at the nadir (ZT16). We will further investigate using Bmal1 knockout mice, Nr1d1 knockout mice, Bmal1-lKO (liver-specific knockout of Bmal1) and Nr1d1-lKO mice.
