Adipocytes regulate fibroblast function, and their loss contributes to fibroblast dysfunction in inflammatory diseases
Faust H. et al. (bioRxiv) DOI: 10.1101/2023.05.16.540975
● Fibroblasts and Adipocytes
● Joint inflammation
● Cortisol signalling
The healthy synovium consists of cells that make up the soft membrane surrounding the joint cavity. The synovial membrane can be divided into two distinct layers: the inner lining layer forms the physical barrier between the synovial fluid in the joint cavity and the main synovial tissue, which contains the vasculature. The sublining layer, comprised of connective tissue, is the outer layer proximal to the vasculature and adjacent to fat pads, mainly consisting of adipocytes. Adipocytes can respond to local signalling and secrete adipokines and cytokines. Fibroblasts comprise most cells in the synovium, residing in both membrane layers, and are important for maintaining joint homeostasis, lubrication, and integrity. The proximity between fibroblasts and adipocytes suggests a possible close interaction between the two populations, but the mechanism of how they affect one another is not elucidated. Interestingly, adipocytes disappear and are replaced by fibrotic tissue in the synovium of patients with osteoarthritis (OA) and rheumatoid arthritis (RA).
Faust et al. have shown that adipocyte was the main source for driving a healthy fibroblast phenotype by culturing RA synovial fibroblasts in fat or adipocyte-conditioned media. Transcriptomic profiling revealed that healthy donors have enriched genes (APOD+ and PLIN2+) related to fatty acid metabolism, and inflamed patients lose the abundance of this adipocyte population, which is replaced by fibrosis. Remarkably, TNFα, IFN-γ, and TGF-α stimulated fibroblasts showed decreased IL-6 secretion when cultured in fat-conditioned media. They found cortisol as the main molecule required to maintain a healthy fibroblast phenotype using fractionation and mass spectrometry. Using the CRISPR/Cas9 approach, they deleted the glucocorticoid receptor gene (NR3C1) in cultured cells. They validated this in mice where adipocyte depletion led to a significant reduction of Hsd11β1 enzyme, which converts active cortisol from cortisone. Furthermore, the absence of adipocytes in mice led to the loss of healthy fibroblasts and revealed adipocytes as a contributor to cortisol signalling.
· Collection of synovial tissue from healthy donors was conducted in post-mortem dissection, and samples from patients with OA/RA were obtained during surgery. The authors appreciate that this might present possible phenotypic differences, so they collected samples 6 hours post-mortem of healthy donors. Furthermore, they validated the results in mouse models depleted of adipocytes via functional and bioinformatic analyses.
· While the mechanism elucidated in this preprint is not specific to the type of joint disease, the authors may benefit from future experimental designs that investigate the interaction between different subsets of adipocyte and fibroblast. It may demonstrate whether specific adipocyte subsets drive distinct fibroblast pathology in OA or RA, and which subsets are highly involved and closely interacting at different stages of the disease.
· Since the pathogenesis of OA is known to be associated with obesity, it is possible that different adipocyte subsets may regulate other fibroblasts phenotype. Future experiments may benefit authors by introducing donor samples with conditions where adipocytes may be dysregulated.
This study details the mechanisms of emerging appreciated crosstalk between adipocytes and fibroblasts in the joint, highlighting a previously underappreciated immune function of these stromal populations. While the mechanism elucidated in this preprint is specific to synovial fibroblasts and adipocytes, this may be shared in other tissues (i.e., lungs, skin, lymph nodes) where stromal cells are highly involved in homeostasis, inflammation, and cancer. This opens new avenues for studying crosstalk between adipocytes and fibroblasts or other cell types. Furthermore, valuable datasets of the synovium from healthy donors and patients with OA and RA may also benefit other studies involved in inflammation. Current treatment for patients with OA and RA includes pain relief and anti-inflammatory medications. The disease prevalence is high, and many patients who do not respond to treatment may require joint surgery or become disabled. Understanding the mechanism of how joint homeostasis is regulated and can be induced by corticosteroid treatment offers an important insight that can be utilised for better-tailoring therapies to the stage of the disease and the individual.
Reviewed by Micon Garvilles as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute, and the University of Toronto.
The author declares no conflict of interest in relation to their involvement in the review.