Expansion of myeloid-derived suppressor cells contributes to metabolic osteoarthritis through subchondral bone remodeling

Abstract

Background Osteoarthritis (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. Methods In 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. Results We 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. Conclusion These data suggest that MDSCs are reprogrammed in metabolic disease, with the potential to contribute towards OA progression and severity.

Identification of osteoarthritis-characteristic genes and immunological micro-environment features through bioinformatics and machine learning-based approaches

“…The primary cytokines associated with the Th2 subset are interleukin-4 (IL-4) and IL-13. The Th17 phenotype has the capability to generate IL-17, which in turn triggers an autoimmune response and stimulates the activation of neutrophils [ 55 ]. Follicular helper T cells have the capability to express a range of genes associated with inflammation and can additionally stimulate B cells to generate immunoglobulin [ 51 ].…”

Osteoarthritis: pathogenic signaling pathways and therapeutic targets

“…Numerous studies reported that subchondral bone sclerosis could be one of the major reasons that cause aging-related OA and that the abnormal bone remodeling related to dysregulation of osteoblasts and osteoclasts plays key roles in the OA initiation and development. 82 – 87 Increased subchondral bone porosity and remodeling, reduced bone density, and bone mineralization with irregular matrix organization, which were believed to be stimulated by bone-cartilage crosstalk through subchondral pores and vascular invasion, were observed in the early stage of OA. 88 – 91 These changes in subchondral bone were found to be happening at the same time with or earlier than the early destruction of articular cartilage.…”

The role of myeloid derived suppressor cells in musculoskeletal disorders

“…MDSCs mainly generate where myelopoiesis takes place including the bone marrow, spleen, and other lymphatic organs, but they can be also reprogrammed from mature myeloid cells in the periphery (37). Besides their immune modulatory ability, MDSCs can differentiate into mature and functional osteoclasts (61)(62)(63)(64)(65). An in vitro experiment using murine Gr1+CD11b+ MDSCs showed that a combination of RANKL and M-CSF can initiate differentiation into osteoclasts.…”