Metabolic dysregulation accelerates injury‐induced joint degeneration, driven by local inflammation; an in vivo rat study

Abstract

Evidence is growing for the existence of an obesity-related phenotype of osteoarthritis in which low-grade inflammation and a disturbed metabolic profile play a role. The contribution of an obesity-induced metabolic dysbalance to the progression of the features of osteoarthritis upon mechanically induced cartilage damage was studied in a rat in vivo model. Forty Wistar rats were randomly allocated 1:1 to a standard diet or a high-fat diet. After 12 weeks, in 14 out of 20 rats in each group, cartilage was mechanically damaged in the right knee joint. The remaining six animals in each group served as controls. After a subsequent 12 weeks, serum was collected for metabolic state, subchondral bone changes assessed by μCT imaging, osteoarthritis severity determined by histology, and macrophage presence assessed by CD68 staining. The high-fat diet increased statistically all relevant metabolic parameters, resulting in a dysmetabolic state and subsequent synovial inflammation, whereas cartilage degeneration was hardly influenced. The high-fat condition in combination with mechanical cartilage damage resulted in a clear statistically significant progression of the osteoarthritic features, with increased synovitis and multiple large osteophytes. Both the synovium and osteophytes contained numerous CD68 positive cells. It is concluded that a metabolic dysbalance due to a high-fat diet increases joint inflammation without cartilage degeneration. The dysmetabolic state clearly accelerates progression of osteoarthritis upon surgically induced cartilage damage supported by inflammatory responses as demonstrated by histology and increased CD68 expressing cells localized on the synovial membrane and osteophytes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:881-890, 2018.

Imaging of Folate Receptor Expressing Macrophages in the Rat Groove Model of Osteoarthritis: Using a New DOTA-Folate Conjugate

“…We previously showed that the observed progression of joint degeneration in this model was mainly inflammatory driven. 22 We observed a clear increase of activated macrophages in the specific joint tissues compared with sham operated contralateral controls.…”

“… 21 On the other hand, when cartilage damage is mechanically induced in addition to high-fat (HF) diet feeding, an inflammatory driven increase in joint degeneration was observed. 22 The role of folate receptor expressing macrophages in both OA models is currently unknown. We hypothesized that accumulation of the novel folate radioconjugate in the target tissue may be visualized in the rat groove model on both a standard diet and a HF diet.…”

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

“…The animal model most thoroughly examined in the context of metabolic OA is the C57BL/6J mouse strain, or genetic variants based on this background, as the readily obtained obesity observed in C57BL/6J mice closely parallels the metabolic adaptations seen in human disease pathogenesis 11 . Most researchers have employed the very high-fat diet (VHFD), a high-fat diet with a supraphysiological fat content of 60 kcal% energy from fat, to induce metabolic OA in male mice e occasionally combined with an increased mechanical burden through surgery or exercise 12,13 . In contrast, published experimental designs vary greatly in study duration and age at start, which are important determinants of the capacity for metabolic adaptation and ultimately of the severity of metabolic OA.…”

“…Most researchers have employed the very high-fat diet (VHFD), a high-fat diet with a supraphysiological fat content of 60 kcal% energy from fat, to induce metabolic OA in male mice e occasionally combined with an increased mechanical burden through surgery or exercise 12,13 . In contrast, published experimental designs vary greatly in study duration and age at start, which are important determinants of the capacity for metabolic adaptation and ultimately of the severity of metabolic OA.…”

Mechanism research on a bioactive resveratrol–PLA–gelatin porous nano-scaffold in promoting the repair of cartilage defect

“…Articular cartilage defect is a formidable clinical problem with cartilage degeneration or loss, which is difficult to treat and slow to develop. 1,2 When cartilage defects occur, there is no support for new cartilage growth to climb in or across the defect. Furthermore, the defect interval is too wide for the chondrocytes to migrate.…”