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Hydrogel-guided p-LOX nanodrug delivery modulates metabolic microenvironment for cartilage repair in osteoarthritis
Yuna Qian1, Sixiang Wang2, Yongqiang Sha3
1National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325001, China.
Abstract:
Osteoarthritis (OA) is a common degenerative disorder characterized by joint inflammation and progressive loss of cartilage. Anti-OA therapies are still lacking. The hallmark of OA pathoetiology is an imbalance in metabolic activities that causes persistent inflammation and an intrinsic loss of regenerative capacity. In the present study, we discovered that lysyl oxidases (LOXs) were downregulated in clinical samples of patients with OA. LOX supplementation remodeled the metabolic microenvironment via an anti-inflammatory effect. We constructed a positively charged LOX-based (p-LOX) nanodrug delivery system guided by a hydrogel (HG), which consisted of photo-crosslinked hyaluronic acid and dopamine. The HG-p-LOX system delivered sustained release of the p-LOX nanodrug for up to 20 days following a one-time intra-articular administration, which effectively repaired cartilage defects and inhibited the pathoetiology of OA. Mechanistically, we discovered that HG-p-LOX delivery altered the OA microenvironment by targeting glycolysis-mediated lactate production in chondrocytes. p-LOX was observed to exert a hitherto unrecognized role in modulating histone lactylation, which is essential for the transcription of target genes linked to inflammatory conditions. We also used SRY-Box Transcription Factor 9-Cre recombinase mutated estrogen receptor 2/lactate dehydrogenase Afloxed/floxed transgenic mice to validate the critical role of lactate in LOX-mediated inflammation. Thus, the HG-p-LOX nanodrug delivery system may represent a novel drug target and a potential clinical treatment for OA repair.
Insights
Lysyl oxidases (LOXs) show promise for osteoarthritis (OA) treatment. A novel hydrogel-nanodrug system (HG-p-LOX) delivers LOX to repair cartilage and reduce inflammation by targeting cellular metabolism.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Molecular Biology
Background:
- Osteoarthritis (OA) is a degenerative joint disease with limited effective therapies.
- OA pathogenesis involves metabolic dysregulation, inflammation, and impaired cartilage regeneration.
- Lysyl oxidases (LOXs) were found to be downregulated in OA patient samples.
Purpose of the Study:
- To investigate the therapeutic potential of LOX supplementation in OA.
- To develop a novel drug delivery system for sustained intra-articular LOX delivery.
- To elucidate the mechanism of LOX action in the OA microenvironment.
Main Methods:
- Construction of a hydrogel-based (HG) positively charged LOX nanodrug (p-LOX) delivery system.
- Intra-articular administration of the HG-p-LOX system in an OA model.
- Analysis of cartilage repair, inflammation markers, and chondrocyte metabolism.
- Investigation of LOX's role in histone lactylation and lactate production using transgenic mice.
Main Results:
- The HG-p-LOX system provided sustained p-LOX release for 20 days.
- Intra-articular administration effectively repaired cartilage defects and inhibited OA progression.
- HG-p-LOX targeted glycolysis-mediated lactate production in chondrocytes.
- p-LOX modulated histone lactylation, impacting inflammatory gene transcription.
Conclusions:
- The HG-p-LOX nanodrug delivery system offers a promising strategy for OA treatment.
- Targeting lactate metabolism and histone lactylation presents a novel therapeutic approach for OA.
- This system demonstrates potential for clinical application in cartilage repair and OA management.
