Hyperlipidemia in tendon injury: chronicles of low-density lipoproteins

**Background:** Hyperlipidemia, characterized by elevated lipid levels, is a known risk factor for cardiovascular disease and has been increasingly associated with musculoskeletal and tendon pathologies, including rotator cuff tendon injury (RCTI). Clinical studies have shown that patients with tendinopathy often have higher circulating cholesterol, LDL, and triglycerides, with reduced HDL levels. However, the molecular mechanisms linking hyperlipidemia to tendon injury remain poorly understood. This review focuses on the role of LDL and oxidized LDL (oxLDL) signaling in the comorbidity of hyperlipidemia and RCTI.

**Methods:** This is a narrative review that synthesizes findings from clinical studies, animal models, and in vitro experiments to elucidate the cellular and biochemical mediators involved in hyperlipidemia-associated tendon injury. The review discusses the structure and function of rotator cuff tendons, the pathophysiology of hyperlipidemia, and the molecular pathways of LDL and oxLDL, including receptor-mediated endocytosis, oxidative modification, and downstream inflammatory signaling. Key studies cited include a cohort of 5,856 individuals showing that hypercholesterolemia (total cholesterol >5 mmol/L) increased the risk of upper extremity tendon injury by 1.5-fold, and metabolic syndrome increased it by 2.5-fold (Skovgaard et al. 2021). Another study involving 49,914 subjects reported a strong association between hyperlipidemia/obesity and RCTI incidence and progression (Macchi et al. 2020).

**Key Results:** The review highlights several important findings: (1) Elevated LDL and oxLDL levels are correlated with increased tendon injury risk, as seen in studies where patients with Achilles tendon repair had significantly higher total cholesterol, LDL-C, and triglycerides compared to controls (Ozgurtas et al. 2003; Yang et al. 2020). (2) OxLDL triggers inflammatory responses by activating endothelial cells, upregulating adhesion molecules, and promoting monocyte adhesion and macrophage differentiation. Macrophages then upregulate toll-like receptors (TLRs) and scavenger receptors, leading to ROS production and matrix degradation. (3) OxLDL also acts as a ligand for RAGE, accelerating lipid deposition and foam cell formation, and activating NF-κB, which upregulates pro-inflammatory mediators. (4) In animal models, ApoE knockout mice fed a high-fat diet showed increased oxLDL deposition in load-bearing tendon ECM and upregulation of MMP2, leading to altered tendon structure (Grewal et al. 2014). (5) High cholesterol induces apoptosis and autophagy in tendon-derived stem cells (TDSCs) via ROS-activated AKT/FOXO1 signaling, and inhibits tendon-related gene expression (Li et al. 2020). (6) Clinical studies show that LDL levels independently impact patellar tendon stiffness, with hyperlipidemic patients exhibiting higher shear wave velocities (Torgutalp et al. 2020). (7) Xanthoma formation, common in familial hypercholesterolemia, is associated with increased intracellular lipid content and inflammatory responses to oxLDL, and antibodies against oxLDL correlate with Achilles tendon thickness (Tsouli et al. 2006).

**Clinical Implications:** The review underscores that hyperlipidemia significantly alters tendon pathophysiology, particularly through LDL and oxLDL signaling, leading to ECM disorganization, inflammation, and increased risk of RCTI. These findings suggest that managing lipid levels, especially LDL, may be crucial in preventing or mitigating tendon injuries. The identification of molecular targets such as RAGE, TLRs, and NF-κB pathways offers potential therapeutic opportunities. However, the exact mechanisms remain unclear, warranting further research to develop novel strategies for RCTI management in hyperlipidemic patients.