In a groundbreaking study published in Nature Communications, researchers led by Zhou, H., Xiao, Y., and Xue, X., have uncovered a crucial molecular mechanism that links hyperglycemia, a hallmark of diabetes, to the exacerbation of osteoarthritis (OA). This study elucidates how elevated blood glucose levels impair the process of macrophage efferocytosis, a vital physiological function responsible for clearing dead and dying cells, through the modulation of CD11b lactylation. Such insights not only deepen our understanding of OA pathogenesis but also reveal new therapeutic targets for managing this debilitating joint disease, which affects millions worldwide.
Osteoarthritis is a common degenerative joint disorder characterized primarily by cartilage degradation, synovial inflammation, and subchondral bone remodeling. While traditionally viewed as a “wear-and-tear” disease, accumulating evidence highlights the significant role of metabolic factors, including diabetes and hyperglycemia, in its progression. However, the precise molecular interplay linking metabolic dysregulation and joint degeneration has remained largely elusive until now. The team’s findings shed light on how chronic elevation of blood sugar levels triggers an inflammatory cascade by hampering macrophage function, thus accelerating joint destruction.
Central to the study’s discoveries is the process of efferocytosis—the efficient engulfment and clearance of apoptotic cells by macrophages. This mechanism is essential for maintaining tissue homeostasis and resolving inflammation. When efferocytosis falters, dead cells accumulate, causing secondary necrosis that releases pro-inflammatory contents, exacerbating tissue injury. The researchers demonstrated that hyperglycemia impairs macrophage efferocytosis through a previously unappreciated biochemical modification: CD11b lactylation.
CD11b is an integrin molecule extensively expressed on the surface of macrophages, crucial for mediating cell adhesion and phagocytosis. Lactylation is a newly identified post-translational modification involving the addition of lactate-derived groups to lysine residues on proteins, profoundly impacting their function. This study provides compelling evidence that elevated glucose levels augment CD11b lactylation, thereby disrupting its normal activity and ultimately hindering macrophage efferocytosis. This effect was verified in both in vitro cellular models and animal studies replicating hyperglycemic conditions.
Through meticulous biochemical assays, the researchers elucidated that hyperglycemia-induced lactate accumulation boosts intracellular lactylation of CD11b, altering its structural conformation and impairing ligand binding capacity. Such impaired receptor functionality decreases the macrophage’s ability to recognize and engulf apoptotic chondrocytes and synovial cells, thereby aggravating synovial inflammation and cartilage degradation in osteoarthritis. This mechanistic insight offers a direct molecular link between metabolic disturbances and joint inflammation, challenging the long-standing paradigm of osteoarthritis pathophysiology.
Further examination of joint tissues revealed that mice with experimentally induced hyperglycemia exhibited significantly increased CD11b lactylation levels concomitant with worsened OA scores compared to euglycemic controls. Histological analyses corroborated these findings, displaying amplified synovial thickening and cartilage erosion. Interestingly, pharmacological interventions that decreased lactylation or enhanced efferocytosis showed promise in mitigating OA severity under hyperglycemic conditions, highlighting potential therapeutic avenues.
Moreover, the study capitalizes on cutting-edge mass spectrometry techniques to precisely map the lactylation sites on CD11b, pinpointing key lysine residues responsible for altered receptor function. The authors propose that targeted inhibition of the enzymes mediating lactylation, such as lactyl-CoA transferases, or modulation of glycolytic flux could serve as strategies to restore macrophage efferocytic capacity, providing a tailored molecular approach to combat diabetic osteoarthritis progression.
Importantly, this research adds a new layer to our evolving understanding of immunometabolism—the intricate cross-talk between metabolic processes and immune cell function. Macrophages, as frontline immune cells, adaptively modify their metabolism in response to environmental cues, which in turn shapes inflammatory outcomes. The revelation that metabolic byproducts like lactate directly modify surface receptors to impair critical functions presents a paradigm shift, opening doors to studies on how metabolic interventions might restore immune homeostasis in chronic inflammatory diseases.
Beyond its implications for OA, the identification of CD11b lactylation as a functional regulator of macrophage activity may also have broader relevance for other conditions characterized by defective efferocytosis and chronic inflammation, such as atherosclerosis, rheumatoid arthritis, and certain fibrotic diseases. This suggests that manipulation of lactylation could become a versatile therapeutic strategy across multiple pathological contexts where macrophage clearance is compromised.
This investigation also underscores the importance of considering systemic metabolic status in the management of osteoarthritis. Patients with concomitant diabetes or metabolic syndrome may experience accelerated joint deterioration due to impaired efferocytosis mediated by hyperglycemia, indicating the need for integrated care approaches that address both glycemic control and joint preservation. Clinicians may need to enhance monitoring and therapeutic strategies for metabolic aberrations to better mitigate OA progression in vulnerable populations.
The study’s multi-dimensional approach—combining cellular, molecular, biochemical, and animal model experiments—provides a robust framework that strengthens the validity of its conclusions. The integration of advanced proteomic methodologies with functional assays enables a comprehensive characterization of the molecular alterations induced by hyperglycemia, representing a state-of-the-art example of biomedical research innovation.
Looking ahead, future research may explore the dynamics of CD11b lactylation in human osteoarthritis patients, potentially through synovial fluid or tissue biopsies, to validate translational relevance. Additionally, screening small molecules or biologics capable of modulating the lactylation pathway could expedite the development of novel disease-modifying osteoarthritis drugs (DMOADs) specifically tailored for patients with comorbid diabetes.
In summary, the work by Zhou et al. compellingly demonstrates that hyperglycemia exacerbates osteoarthritis by impairing macrophage efferocytosis through pathological lactylation of CD11b. This mechanistic insight bridges the gap between metabolic dysfunction and joint degradation, offering fresh targets for therapeutic innovation and emphasizing the critical impact of metabolic health on immune regulation within the osteoarthritic joint. As the global burden of diabetes and osteoarthritis continues to rise, such transformative discoveries will be essential to formulating effective, targeted interventions that can improve patient outcomes.
Subject of Research: The study focuses on the molecular mechanisms by which hyperglycemia exacerbates osteoarthritis, particularly investigating how elevated glucose levels impair macrophage efferocytosis via modulation of CD11b lactylation.
Article Title: Hyperglycemia exacerbates osteoarthritis by impairing macrophage efferocytosis through modulation of CD11b lactylation.
Article References:
Zhou, H., Xiao, Y., Xue, X. et al. Hyperglycemia exacerbates osteoarthritis by impairing macrophage efferocytosis through modulation of CD11b lactylation. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67473-2
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Tags: cartilage degradation mechanismsCD11b lactylation effectschronic inflammation and joint destructiondiabetes and joint healthhyperglycemia and osteoarthritisinflammation in osteoarthritis progressionmacrophage efferocytosis dysfunctionmetabolic factors in joint diseasemolecular mechanisms of osteoarthritisrole of macrophages in joint healththerapeutic targets for osteoarthritistreatment strategies for osteoarthritis
