The mechanisms underlying the effect of obesity on tissue macrophage activity and the cellular microenvironment in osteoarthritis

ABSTRACT. Osteoarthritis (OA) was previously considered primarily a degenerative disease associated with joint “wear and tear.” Nevertheless, recent studies indicate that chronic, low-grade inflammation is a central factor in its development. The aim of this review is to characterize the morphology of inflammation in OA, focusing on macrophage polarization mechanisms and the role of obesity. A literature review of the last 5 years was conducted using PubMed, MEDLINE, and eLibrary databases. The analysis focused on pathogenetic mechanisms of joint damage, macrophage polarization, and obesity’s impact on disease progression. The results of the analysis allow us to conclude that the morphology of inflammation in OA reflects a complex network of cellular interactions, in which macrophage polarization plays a pivotal role, and obesity serves as one of the factors precipitating this process.

For citation: Vakilov FF, Piatnitskaia SV, Shchekin VS, Yakupov RR, Gizatullina RR, Tyurin AV. The mechanisms underlying the effect of obesity on tissue macrophage activity and the cellular microenvironment in osteoarthritis. Therapy (Moscow). 2026;12(5S):124–131. 
https://doi.org/10.18565/therapy.2026.5-s5.124-131

RELEVANCE

Osteoarthritis (OA) is a common chronic joint disease that poses a global healthcare challenge and requires further research to develop effective methods of diagnosis, treatment, and prevention. OA affects more than 300 million people worldwide and is projected to become one of the leading causes of disability by 2030 because of increasing life expectancy and the growing prevalence of excess body weight [1]. In Russia, approximately 13% of the population older than 18 years have knee or hip OA. The true number of patients with OA in the country may reach 14–16 million because official statistics include only diagnosed and registered cases. The incidence of newly diagnosed OA has increased. In Russia, this rate rose by 18% between 2015 and 2024 (from 546.9 to 650.0 per 100,000 population). Regional differences are evident: incidence rates are lower in southern regions, such as the North Caucasus, and higher in northern regions and Eastern Siberia [2].

OA was previously regarded primarily as a degenerative disease associated with joint “wear and tear.” However, current evidence confirms that chronic low-grade inflammation plays a key role in its development and progression [3]. The pathogenesis of OA is complex and involves multiple processes, including immunoinflammatory mechanisms mediated by numerous cellular effectors whose functions remain incompletely understood [4]. The cellular interactions and signaling pathways involved in OA pathogenesis therefore remain the subject of active research [5]. One insufficiently studied aspect of the inflammatory response is the activity of tissue macrophages and their M1 and M2 phenotypes. Depending on the stimuli they encounter, macrophages may acquire either a pro-inflammatory (M1) or an anti-inflammatory (M2) phenotype.

Obesity plays a major role in polarizing macrophages toward a pro-inflammatory phenotype, thereby contributing to OA progression [6]. Pro-inflammatory cytokines – interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) – and adipokines such as leptin, resistin, and visfatin are secreted by adipocytes in visceral adipose tissue. These mediators can reach the synovium and activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome [7]. Its activation, in turn, promotes macrophage polarization toward the M1 phenotype [8]. A deeper understanding of these pathways, including the effects of obesity and macrophage polarization, may facilitate the development of new disease-modifying therapeutic strategies.

Aim: to characterize the morphology of inflammation in OA, with a focus on the mechanisms of macrophage polarization and the role of obesity.

CELLULAR COMPOSITION OF CARTILAGE AND THE SYNOVIAL MEMBRANE IN OSTEOARTHRITIS

Under normal conditions, cartilage consists of chondrocytes and the extracellular matrix (ECM). Articular cartilage is characterized by a low number of cells relative to the volume of the ECM. Chondrocytes account for only 1–2% (up to 5% according to some reports) of the total volume, whereas the ECM accounts for the remaining 98–99%. The mean chondrocyte density in adult human cartilage is estimated at approximately 100 million cells per cubic centimeter. Chondrocytes occur individually or in isogenic groups known as chondrons [9]. Articular cartilage contains several distinct chondrocyte subtypes: proliferative, prehypertrophic (pre-HTC), hypertrophic, and fibrocartilaginous chondrocytes. Proliferative chondrocytes are found predominantly in the proliferative zone, whereas pre-HTCs regulate the initiation of hypertrophic differentiation. Hypertrophic chondrocytes, in turn, help regulate ECM mineralization [10]. More recently, two additional cell types have been identified: senescent cells (SCs) and cartilage progenitor cells. Studies have shown that SCs, which emerge in cartilage during OA, undergo cell-cycle arrest and exhibit a senescence-associated secretory phenotype. These cells secrete pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), matrix metalloproteinases (MMP-1, MMP-3, and MMP-13), and aggrecanases (ADAMTS-4 and ADAMTS-5). Selective elimination of SCs slows OA progression [11].

Fan Y. et al. found that four cell populations predominated in patients with OA (fibrocartilaginous chondrocytes, inflammatory chondrocytes, preinflammatory chondrocytes, and pre-HTCs), whereas only one population – homeostatic chondrocytes – was identified in individuals without OA [12]. Accumulating evidence suggests that pre-HTCs may play a key role in OA pathogenesis. Further subcluster analysis by Fan Y. et al. identified four putative pre-HTC subpopulations. Pre-HTC-1 cells show high expression of marker genes associated with various metal ions, including cadmium, such as MT1G and MT1M. These genes encode metallothioneins, cysteine-rich, low-molecular-weight proteins that protect cells from metal toxicity by forming stable metal complexes. This subpopulation has also been referred to...

F.F. Vakilov, S.V. Piatnitskaia, V.S. Shchekin, R.R. Yakupov, R.R. Gizatullina, A.V. Tyurin