Neprilysin: The Peptide-Degrading Enzyme That Affects Bones, Cartilage, and Muscles

This is a narrative review paper that synthesizes findings from preclinical animal studies, cell culture experiments, and clinical observations about neprilysin's role in musculoskeletal biology and disease. No new experiments were conducted.

Neprilysin is already a drug target in cardiology — sacubitril/valsartan (Entresto) is widely prescribed for heart failure. This review highlights that the same enzyme has important but underappreciated roles in bones, cartilage, and muscles. Understanding these effects matters because millions of patients taking NEP-targeting heart drugs may experience musculoskeletal effects, and these drugs could potentially be repurposed for orthopedic conditions.

The peptide-degrading enzyme neprilysin sits at the intersection of cardiology, pain medicine, and orthopedics. As NEP inhibitors like sacubitril become more widely used for heart failure, understanding their effects on the musculoskeletal system becomes increasingly important. This review suggests that targeting NEP could open new treatment avenues for conditions like osteoarthritis, chondrodysplasia, and sarcopenia — but the direction of intervention (inhibition vs activation) matters depending on the tissue.

As a narrative review, this paper does not include new experimental data or a systematic search methodology. Most evidence discussed comes from animal models and cell culture, with limited human clinical data for musculoskeletal applications specifically. The review does not include meta-analysis or quality assessment of the cited studies.