Initial Responses of Articular Tissues in a Murine High-Fat Diet-Induced Osteoarthritis Model: Pivotal Role of the IPFP as a Cytokine Fountain

Abstract

Obesity and high body mass index are associated with a higher incidence of osteoarthritis (OA). The aim of this study is to investigate the involvement of the infrapatellar fat pad (IPFP) in the sub-acute effect of a high fat diet (HFD) on the development of knee-OA. C57BL/6J male mice were fed either a HFD or a normal diet beginning at seven weeks of age. Tissue sections were evaluated with immunohistological analysis. The IPFP was excised, and mRNA expression profiles were compared using real-time RT-PCR analysis. Osteoarthritic changes were initiated in the HFD group after eight weeks of the HFD. Increased synovial cell number and angiogenesis at the anterior edge of the tibial plateau were exhibited prior to osteophyte formation. Quantitative histological analysis indicated that osteophyte volume was significantly increased in the HFD group after eight weeks, along with an increase in the IPFP volume, the size of individual adipocytes and the number of vessels in the IPFP. Histomorphometrical analysis revealed osteophyte area was significantly associated with IPFP area, individual adipocyte area and vascular area. Real-time RT-PCR analysis demonstrated elevated mRNA expression of inflammatory cytokines, growth factor, and adipokines in the IPFP after eight weeks of the HFD. These findings are in parallel with increased expression of the CD68 macrophage marker after eight weeks of the HFD. Expression levels of the adipokines were significantly correlated with expression of TNF-α, VEGF and TGF-β. Immunohistological analysis revealed that the Nampt protein was highly expressed in the IPFP especially around the site of osteophyte formation. Apoptosis and proliferation of chondrocytes were both enhanced at the site of osteophyte formation, indicating higher cell turnover at this region. These observations suggest the IPFP plays a pivotal role in the formation of osteophytes and functions as a secretory organ in response to a HFD.

Knee and hip intra-articular adipose tissues (IAATs) compared with autologous subcutaneous adipose tissue: a specific phenotype for a central player in osteoarthritis

“…IFP volume9 and release of tumour necrosis factor α by IFP8 are both positively associated with the body mass index (BMI) of human patients with OA. Similarly, in mice fed a high-fat diet, weight gain and IFP volume were correlated with development of OA 10. Positive associations were also found between adipocyte area and vascular infiltrates of IFP 10.…”

“…Similarly, in mice fed a high-fat diet, weight gain and IFP volume were correlated with development of OA 10. Positive associations were also found between adipocyte area and vascular infiltrates of IFP 10. Consequently, IFP may have a paracrine function in other joint tissues in OA, especially the adjacent synovium 5 6…”

Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought

“…A HFD is known to increase these inflammatory OA features in mice 18,19 , which can be distinguished before changes in cartilage structure become visible 20 . In general, both features showed high variability in our studies (Figs.…”

Alterations in Hoffa’s fat pad induced by an inflammatory response following idealized anterior cruciate ligament surgery

“…Adipose tissues are known to release both cytokines and growth factors [36]. In fact, the gross morphological disturbances in the knee joint 2 weeks post-ACL-R surgery have been positively correlated to the inflammatory biomarker IL-6 mRNA levels ( Table 2).…”