Dissecting the influence of the components of metabolic syndrome on clinical, ultrastructural, and molecular knee osteoarthritis phenotypes

• Applicants: Privatdozent Dr. Christian Ries; Privatdozent Dr. Tim Rolvien
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563999709

Osteoarthritis (OA) is a chronic disease characterized by a gradual loss of joint cartilage, resulting in a loss of joint function that clinically manifests as limited mobility and pain. OA affects more than 500 million people worldwide, with the knee being the most commonly affected joint and obesity being a major risk factor. Many obese people also develop other conditions such as insulin resistance (type 2 diabetes mellitus), high blood pressure (hypertension) and dyslipidemia, a complex of conditions known as metabolic syndrome. In recent years, it has become apparent that not only obesity itself may be a direct (mechanical) risk factor for OA, but that various conditions related to the key components of the metabolic syndrome may also play a crucial mechanistic role in OA development. However, because a nuanced understanding of how the components of metabolic syndrome influence the development of OA at the structural, cellular, and molecular levels is still largely lacking, this research project will combine clinical assessments, multiscale osteochondral biopsy analyses, and targeted proteomic and cell culture approaches. First, patients with and without metabolic syndrome undergoing knee arthroplasty will be systematically assessed pre- and postoperatively. Physician and patient-related outcomes will be recorded, with a focus on clinical outcomes and patient dissatisfaction. In addition, bone-cartilage specimens will be collected, evenly distributed among patients with primary OA, obesity alone and metabolic syndrome during knee arthroplasty. We will assess clinical knee OA phenotypes (radiographs), articular cartilage (OARSI score, thickness, mineralization) and the subchondral bone using µ-CT, undecalcified histomorphometry, quantitative backscatter electron imaging, and nanoindentation, and osteocyte lacunocanalicular network characterization. Furthermore, a targeted proteomic analysis of synovial fluid will be performed, and gene expression of relevant cartilage and bone genes will be analyzed in resected tissue samples. As recent evidence has shown that bone marrow subchondral adipose tissue (BMAT) may be involved in OA pathogenesis, specific alterations of BMAT and its effects on cartilage status and especially subchondral bone remodeling will be characterized and stratified according to the presence of metabolic syndrome components. Finally, based on promising identified candidates at the gene and protein level, the effect of cytokines, hormones and adipokines on cartilage homeostasis will be investigated in vitro using conventional cell cultures and advanced cartilage organoid models. With the knowledge gained, we aim to lay the foundation for the development of OA prevention strategies in metabolic syndrome, targeting relevant mechanisms and focusing on subchondral bone as a promising target.

• DFG Programme: Research Grants