Work

LNA043 and ANGPTL3 Interactions with Integrin α5β1 and Fibronectin Drive Distinct Stromal and Immune Responses

Year: 2026

Type: preprint

Abstract: Osteoarthritis (OA) is characterized by cartilage breakdown, extracellular matrix remodeling, and synovial inflammation. Dysregulated integrin α5β1 signaling and fibronectin fragmentation are key drivers of OA progression. We found that in ihMSC, LNA043, Full length ANGPTL3 (FL-ANGPTL3), and C-terminal fibrinogen like domain of ANGPTL3 (C-ANGPTL3) interacted with both integrin α5β1 and fibronectin, consistent with a multivalent binding mode supported by AlphaFold based structural predictions. FL-ANGPTL3 supported ihMSC adhesion and induced human monocyte migration, with both effects being dependent on integrin β1. C-ANGPTL3 alone was sufficient to mediate these effects, although with reduced efficacy compared to the full-length protein. In contrast, LNA043 did not support ihMSC adhesion but retained integrin β1-dependent monocyte migratory activity, defining a more selective functional profile and indicating that further truncation modulates downstream responses without abolishing integrin engagement. To further explore the biology of ANGPTL3 and the mechanism of action of LNA043 we employed a targeted RASL Seq profiling. We found that both FL- and C-ANGPTL3, but not LNA043, induced broad transcriptional reprogramming and counter regulated fibronectin fragment–driven inflammatory signaling in monocytes. We uncovered a role for ANGPTL3 in fibronectin-integrin α5β1 signaling and showed that LNA043 preserves this interaction while uncoupling it from strong immune responses.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.14.751366