A study published in Nature Communications reveals a novel mechanism by which hyperglycemia exacerbates osteoarthritis (OA). Researchers discovered that high blood sugar enhances glycolysis in synovial macrophages, leading to lactate accumulation and subsequent lactylation modification at the K575 site of the macrophage surface receptor CD11b. This post-translational alteration impairs the macrophage's ability to clear apoptotic cells (efferocytosis), fueling chronic synovial inflammation and joint degeneration. The acetyltransferase CBP was identified as the enzyme catalyzing this modification. Notably, the CD11b geneknockout THP1 cells, constructed by HySigen Bioscience using CRISPR-Cas9 RNP technology, served as a pivotal genetic tool to establish causality in thisresearch.

Fig. 6 CD11b K575 lactylation alters its structure, reduces macrophage recognition of apoptotic cells, and impairs efferocytosis function

Multidimensional Research Approach

• Clinical & Animal Models: Analysis of synovial tissues from diabetic OA patients and hyperglycemic OA mouse models.

• Cellular Studies: Macrophages derived from patient PBMCs cultured undernormo-/hyperglycemic conditions; functional efferocytosis assays.

• Metabolic &Molecular Analysis: Seahorse assays to quantify glycolysis; Co-IP/MS to identify lactylated proteins and interacting enzymes.

• Structural Simulation: Molecular dynamics (MD) simulations to model how CD11b K575 lactylation alters protein conformation and weakens binding to apoptotic cellmarkers.

• Therapeutic Validation: In vivo use of glycolysis inhibitor 2-DG and targeted synovialmacrophage knockdown of CBP via rAAV.

HySigen's CD11b-KO THP1 Cells: The Pivotal Tool

This precisely engineered cell line was indispensable for mechanistic dissection, enabling three critical insights:

• Establishing Functional Necessity: Loss of CD11b in KO cells significantly impaired macrophage efferocytosis, providing direct genetic proof that CD11b is essential for this process.

• Decoupling General Loss from Specific Modification: The clean genetic background allowed researchers to express specific CD11b mutants (e.g., K575R) to distinguish the effect of protein absence from the specific functional consequence of K575 lactylation.

• Validating the Therapeutic Axis:The KO model served as a baseline for proving that restoring function via CBP knockdown targets the specific lactylation-dependent pathway, not just general CD11b expression.

✨ Key Takeaway: This research defines the pathogenic axis" hyperglycemia → enhanced glycolysis → CD11b K575 lactylation → impaired efferocytosis → worsened OA. " The CD11b-KO THP1 cell line provided the essential genetic precision to transform biochemical observations into avalidated causal mechanism, solidifying CBP as a promising therapeutic targetfor slowing OA progression in diabetic patients.

Publication: Zhou H, Xiao Y, Xue X, et al. Hyperglycemia exacerbates osteoarthritis by impairing macrophage efferocytosis through modulation of CD11b lactylation[J]. Nature Communications, 2025. https://doi.org/10.1038/s41467-025-67473-2

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