Role of mechanical signals for growth and regeneration of bones / LR signaling in aging and joint trauma as a potential cause of osteoarthritis

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Our laboratory investigates the cellular and molecular causes of osteoarthritis, the most common joint disease in adults worldwide. To date, there is no therapy that alters the course of the disease. The onset of osteoarthritis is closely associated with advanced age and joint trauma, and the signaling pathways involved are still poorly understood. Therefore, we aim to gain a better understanding of the control of cartilage and bone formation and degradation in joints during aging and trauma. We will first study these processes in the healthy state and then compare them with their regulation in osteoarthritis. The focus here is on the cartilage-forming cells, the chondrocytes, as well as the cells of the synovial membrane and the subchondral bone. The changes in cartilage and bone metabolism identified in this way offer potential targets for causal therapies by biological regeneration of articular cartilage.

Project description – Project 1:

Role of mechanical signals for growth and regeneration of bones

In a recent study, we found that mechanical loading regulates bone growth. This is achieved by controlling angiogenesis and bone mineralization in the ossification front – growth plate region and also in subchondral bone via mechanical forces.¹ However, how mechanical force is perceived molecularly is still not fully understood. Based on our data and recent publications,^2,3 mechano-responsive ion channels of the PIEZO family appear here as promising mechano-receptor candidates. Given the importance of mechanical cues in bone regeneration,⁴ we aim to investigate the role of PIEZO molecules and their signaling pathways in the regulation of bone growth and bone healing in this project.

Project description – Project 2:

TLR signaling in aging and joint trauma as a potential cause of osteoarthritis

Our current data show that stimulation of specific Toll-like receptors (TLRs) severely impairs the mitochondrial respiratory chain and cartilage production of human chondrocytes (Shen et al., submitted). We hypothesize that age- or joint-trauma-induced degradation processes release cartilage fragments that activate specific TLR molecules. Chondrocytes respond by amplifying their TLR signaling pathways. This causes an energy and metabolic deficit and triggers further cartilage degradation, which could ultimately lead to osteoarthritis. To further investigate changes in TLR signaling and metabolic pathways, we plan to perform RNA sequencing of human chondrocytes from the following donors: 1) young, healthy; 2) young, post-traumatic osteoarthritis; 3) older, healthy; 4) older, age-associated osteoarthritis. Comparisons of the transcriptomes should reveal age-related changes in healthy cartilage as well as shifts in age- and trauma-associated osteoarthritis.

Application details

References

1. Dzamukova M, Brunner T, Miotla-Zarebska J, […], Schinke T, Vincent T, Löhning M. Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth. Nat Commun. 2022; 13:3059. doi: 10.1038/s41467-022-30618-8.
2. Li X, Han L, Nookaew I, […], Silva MJ, Almeida M, Xiong J. Stimulation of Piezo1 by mechanical signals promotes bone anabolism. eLife. 2019; 8:e49631. doi: 10.7554/eLife.49631.
3. Sun W, Chi S, Li Y, […], Liu Z, Xiao B, Li Y. The mechanosensitive Piezo1 channel is required for bone formation. eLife. 2019; 8:e47454. doi: 10.7554/eLife.47454.
4. McDermott AM, Herberg S, Mason DE, […], Kelly DJ, Alsberg E, Boerckel JD. Recapitulating bone development through engineered mesenchymal condensations and mechanical cues for tissue regeneration. Sci. Transl. Med. 2019; 11:eaav7756. doi: 10.1126/scitranslmed.aav7756.