Research

Identification of TLR signaling as novel risk factor and treatment target in osteoarthritis using single-cell RNA sequencing

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. In Germany, more than 5 million patients suffer from OAand there is no effective treatment1. Among several risk factors for OA development, age has the greatest influence2. In parallel, individuals who bear joint injury are at substantially increased risk of OA, the so-called posttraumatic OA (PTOA)3. However, the signaling pathways that propagate the pathogenic aspects of age and trauma are ill defined. Cellularly, the alteration of chondrocyte biology plays a key role in OA pathogenesis4. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can function as agonist of Toll-like-receptors (TLR). We have found that chondrocytes adapt to this setting by enhanced TLR signaling, which results in impaired matrix generation and energy deficit. This suggests that individuals with high TLR activity in chondrocytes have an increased risk of OA.

However, chondrocytes are not a homogenous population. Classically, according to their cartilage zonal locations, chondrocytes are subdivided into superficial, middle, and deep zone chondrocytes. These zonal subsets exhibit distinct transcriptome profiles5. Our recent scRNAseq analysis, together with two other studies, of human chondrocytes revealed an even higher heterogeneity and identified seven subsets6. Importantly, the composition of these subsets varies during OA progression6. Thus, we aim to effectively manipulate human chondrocytes in vivo in order to regenerate and restore cartilage integrity. Therefore, we seek to identify the evolution of the transcriptional programs of chondrocytes, with a particular focus on TLR signaling, during ageing and PTOA development at single-cell resolution. We plan to perform scRNAseq analysis of chondrocytes isolated from individuals (5 each) of young healthy (YH), PTOA, old healthy (OH), and old age-related OA (OAOA). Herewith we will address ① an overall chondrocyte compositional alteration during ageing and OA development; ② whether TLR and its signaling components qualify as risk factor of (PT)OA and hence whether TLR signaling inhibition may prevent OA progression; ③ the design of a treatment strategy to specifically deliver the inhibitory agents to the TLR-expressing chondrocyte subsets and/or TLR-expressing cartilage zones.

Application details

References

  1. Grifka J, Ogilvie-Harris DJ. Osteoarthritis: Fundamentals and Strategies for Joint-Preserving Treatment. Springer. 2010.
  2. Martel-Pelletier J, Barr AJ, Cicuttini FM, […], Jones G, Teichtahl AJ, Pelletier JP. Osteoarthritis. Nat Rev Dis Primers. 2016; 2:16072. doi: 10.1038/nrdp.2016.72.
  3. Jiménez G, Cobo-Molinos J, Antich C, López-Ruiz E. Osteoarthritis: Trauma vs Disease. Adv Exp Med Biol. 2018; 1059:63-83. doi: 10.1007/978-3-319-76735-2_3.
  4. Sook Hwang H, Kim HA. Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis. Int J Mol Sci. 2015; 16:26035-26054. doi: 10.3390/ijms161125943.
  5. Grogan SP, Duffy SF, Pauli C, […], Su AI, D´Lima DD, Lotz MK. Zone-specific Gene Expression Patterns in Articular Cartilage. Arthritis Rheum. 2013; 65:418-428. doi: 10.1002/art.37760.
  6. Ji Q, Zheng Y, Zhang G, […], Xu Y, Wang Y, Tang F. Single-cell RNA-seq Analysis Reveals the Progression of Human Osteoarthritis. Ann Rheum Dis. 2019; 78(1):100-110. doi: 10.1136/annrheumdis-2017-212863.