Abstract
BackgroundOsteoarthritis (OA) subsequent to acute joint injury accounts for a significant proportion of all arthropathies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells classically known for potent immune-suppressive activity; however, MDSCs can also differentiate into osteoclasts. In addition, this population is known to be expanded during metabolic disease. The objective of this study was to determine the role of MDSCs in the context of OA pathophysiology.MethodsIn this study, we examined the differentiation and functional capacity of MDSCs to become osteoclasts in vitro and in vivo using mouse models of OA and in MDSC quantitation in humans with OA pathology relative to obesity status.ResultsWe observed that MDSCs are expanded in mice and humans during obesity. MDSCs were expanded in peripheral blood of OA subjects relative to body mass index and in mice fed a high-fat diet (HFD) compared to mice fed a low-fat diet (LFD). In mice, monocytic MDSC (M-MDSC) was expanded in diet-induced obesity (DIO) with a further expansion after destabilization of the medial meniscus (DMM) surgery to induce post-traumatic OA (PTOA) (compared to sham-operated controls). M-MDSCs from DIO mice had a greater capacity to form osteoclasts in culture with increased subchondral bone osteoclast number. In humans, we observed an expansion of M-MDSCs in peripheral blood and synovial fluid of obese subjects compared to lean subjects with OA.ConclusionThese data suggest that MDSCs are reprogrammed in metabolic disease, with the potential to contribute towards OA progression and severity.
Highlights
Osteoarthritis (OA) is a highly prevalent and disabling disease that remains a challenge to develop effective therapeutics primarily since there is a limited understanding of the early-stage disease which results in later-stageZhang et al Arthritis Research & Therapy (2021) 23:287 which both promote inflammation in the synovium and participate in cartilage damage [3]
high-fat diet (HFD) promotes DMM‐induced OA disease pathology To investigate the effect of HFD on cartilage, we used the post-traumatic OA (PTOA) model induced by surgical destabilization of the medial meniscus (DMM) after mice were fed an HFD or micronutrient matched low-fat diet (LFD) for 12 weeks
HFD alters subchondral bone parameters To understand if in vitro osteoclastogenesis observations translated into exacerbated DMM-induced pathology during the metabolic stress of obesity, we examined the subchondral bone for pathological changes in DMM mice on HFD versus LFD controls
Summary
Osteoarthritis (OA) is a highly prevalent and disabling disease that remains a challenge to develop effective therapeutics primarily since there is a limited understanding of the early-stage disease which results in later-stageZhang et al Arthritis Research & Therapy (2021) 23:287 which both promote inflammation in the synovium and participate in cartilage damage [3]. Evidence that innate and adaptive immune systems play roles in the post-traumatic joint exists, with increases in activated macrophages, CD4+ T cells, complement (C3a), and inflammatory cytokines described in injured knee joints [5] Despite this knowledge, current therapies for OA are restricted and no treatment has been conclusively shown to alter OA disease progression. In addition to the current paradigm of inflammation in OA pathophysiology is the awareness that metabolic disease is associated with OA (termed metabolic osteoarthritis), in part through proinflammatory conditions and oxidative stress [8] This new appreciation of metainflammation and impact in OA creates new challenges and opportunities, especially in this era of precision medicine. The objective of this study was to deter‐ mine the role of MDSCs in the context of OA pathophysiology
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