PGC1alpha in cartilage development and osteoarthritis

• Applicant: Dr. Carina Prein
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Anatomy and Physiology ; Developmental Biology ; Structural Biology
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416004908

Musculoskeletal diseases such as osteoarthritis (OA) have a major impact on individual well-being and our health care system, but are currently poorly managed due to the lack of drugs that can slow or stop disease progression.Nuclear receptors such as peroxisome proliferator-activated receptors (PPAR´s) have become attractive potential targets for pharmacological therapies in the field of musculoskeletal research due to their involvement in vital processes in bone and cartilage development. Since nuclear receptors modulate the expression of specific genes in a ligand dependent manner through the recruitment of cofactors, there is an increasing interest in the role and potential therapeutic usage of PPAR cofactors. The peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is one of those cofactors. PGC1-α was reported to interact with peroxisome proliferator-activated receptor γ, which plays an important role during endochondral ossification, as well as being co-expressed among Sox9, one of the most important transcription factors during chondrogenesis. However, the impact of PGC1-α on cartilage development and aging is unknown.Therefore, our first aim is to investigate the specific role of PGC-1α during cartilage and bone development by using tissue-specific knockout mice. Knockout as well as control mice will be analyzed at relevant time points by validated histological, immunohistochemical, and biomechanical assays. Preliminary analysis at postnatal day 21 showed disturbed growth plate development and skeletal growth due to the lack of PGC-1α. These early developmental changes might influence proper articular cartilage development and maintenance, which we will further analyze in aging studies. In our second aim we will investigate the impact of PGC-1α on the development of spontaneous as well as post-traumatic OA using an inducible knockout mouse line. Post-traumatic OA will be induced by destabilization of the medial meniscus (DMM) surgery model. Beside histological examination of knee joints of DMM and sham mice, we will analyze locomotor activity, and perform catwalk gait analysis, as well as micro-CT measurements. Furthermore, since PGC-1α might be involved in various signaling pathways regulating proper cartilage matrix composition, development, and homeostasis, we will perform atomic force microscopy imaging and indentation measurements to analyze the impact of the loss of PGC-1α on cartilage structural and biomechanical properties in our different knockout models as well as in our post-traumatic OA model. Collectively these studies will determine the roles and potential therapeutic implications of PGC-1α in skeletal development and osteoarthritis.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Professor Dr. Frank Beier