A review of neprilysin — an enzyme that breaks down key peptides like natriuretic peptide and substance P — reveals its wide-ranging roles in bone growth, cartilage repair, muscle development, and pain regulation in musculoskeletal diseases.
Tissue-specific effectsNEP inhibitors promote bone/cartilage growth but NEP activators promote muscle growth — opposite directions depending on the target tissue
What the researchers found
The review identifies several key roles for neprilysin in musculoskeletal health. NEP degrades pro-inflammatory neuropeptides like substance P, reducing local inflammation in joints and muscles. It also breaks down endogenous opioids, playing a role in pain regulation.
In stem cell research, NEP promotes osteogenic (bone), chondrogenic (cartilage), and myogenic (muscle) differentiation of mesenchymal stem cells. The NEP inhibitor sacubitril promotes cartilage growth plate thickening and bone growth in animal models of chondrodysplasia, while NEP activators — rather than inhibitors — promote muscle growth in castrated rats. This tissue-specific directional difference is an important finding.
Why it matters
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.
How the study worked
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.
What this study cannot tell us
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.
How to read the evidence
This is a narrative review synthesizing existing preclinical and clinical literature. It provides a useful overview but does not generate new evidence. Most findings are from animal models, limiting direct clinical applicability.
When this study was published
Published in 2026 in Tissue & Cell, this is a very recent review capturing the latest understanding of neprilysin's musculoskeletal roles.
The bigger picture
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.
Questions still open
- Do patients on sacubitril/valsartan for heart failure show measurable changes in bone density or cartilage health?
- Could tissue-specific NEP modulators be developed to treat musculoskeletal diseases without affecting cardiovascular peptide signaling?
- What is the optimal balance of NEP activity for simultaneous bone, cartilage, and muscle health?
Common questions
What is neprilysin and what peptides does it break down?
Could heart failure drugs that target neprilysin affect bones and muscles?
Read the original research
The role of neprilysin in musculoskeletal diseases.
Tissue & cell, 99, 103324
Citation
Wu, Zuping; Wang, Ying; Wu, Na; Lu, Mingcheng; Shi, Jiejun. (2026). The role of neprilysin in musculoskeletal diseases.. Tissue & cell, 99, 103324. https://doi.org/10.1016/j.tice.2026.103324