EC Orthopaedics

Osteoarthritis (OA) is a disease characterized by progressive destruction of cartilage although currently, more correctly, considered a disease of whole joint. Increased subchondral bone turnover is a key moment underlying osteoarthritic process determined by an altered relationship between the activity of osteoblasts, osteoclasts, and osteocytes. While the systemic hormonal regulation of the remodeling process has to occur via factors arriving at individual remodeling sites via bloodstream, the way by which local regulatory factors exert their action on individual cell populations has been subject of constant and progressive knowledge. Initial subchondral bone and cartilage damage starts with release of some factors responsible for joint pain. For a long time, the release of NGF from damaged cells in osteochondral junction has been considered as main event and trigger of pain carried, via various nociceptive fibers, to the spinal cord.

Recently other factors have entered this complex mechanism; one of the emerging player is a member of laminin-like protein family, Netrin-1, which was initially identified as a molecule involved in axonal guidance but also in non-neural activities like angiogenesis, inflammation, tissue remodeling and cancer. Netrin-1, as a part of the classic axon guidance family (netrins, semaphorins, ephrins and slits), was shown to coordinate cell migration and axonal growth as a chemoattractant or chemorepellent, depending on the receptors expressed by target cells.

Recent research has revealed a link between Netrin-1 and the development of multiple inflammatory diseases such as ischemic reperfusion injury, atherosclerosis, diabetes. Nonetheless the effects of Netrin-1 are not exactly the same in all disease or inflammatory condition. It has been also found that Netrin-1 orchestrate organogenesis, angiogenesis, tumorigenesis. In inflammation, as in neuronal development, Netrin-1 plays a role directing migration of leukocytes, especially monocytes in inflamed tissues with impact on acute and chronic inflammation.

 Keywords: Netrin-1; Inflammation; Osteoarthritis; Rheumatoid Arthritis

1. Felson DT. “Developments in the clinical understanding of osteoarthritis”. Arthritis Research and Therapy 1 (2009): 203.
2. Burr DB and Gallant MA. “Bone remodelling in osteoarthritis”. Nature Reviews Rheumatology 11 (2012): 665-673.
3. Attur M., et al. “Low grade inflammation in symptomatic knee osteoarthritis”. Arthritis and Rheumatology 11 (2015): 2905-2915.
4. Yusup A., et al. “Bone marrow lesions, subchondral bone cysts and subchondral bone attrition are associated with histological synovitis in patients with end-stage knee osteoarthritis: a cross sectional study”. Osteoarthritis and Cartilage11 (2015): 1858-1864.
5. Zhang Y., et al. “Fluctuation of knee pain and changes in bone marrow lesions, effusions and synovitis on magnetic resonance”. Arthritis and Rheumatology 3 (2011): 691-699.
6. Boyle WJ., et al. “Osteoclast differentiation and activation”. Nature6937 (2003): 337-342.
7. Eriksen EF. “Cellular mechanism of bone remodeling”. Reviews in Endocrine and Metabolic Disorders4 (2010): 219-227.
8. Siddiqui JA and Partridge NC. “Physiological bone remodeling: Systemic regulation and growth factor involvement”. Physiology (Bethesda)3 (2016): 233-245.
9. Xia X., et al. “Netrin-1: An emerging player in inflammatory diseases”. Cytokine and Growth Factor Reviews 64 (2022): 46-56.
10. Chicherova I., et al. “Axon guidance molecules in liver pathology: Journeys on a damaged passport”. Liver International9 (2023): 1850-1864.
11. Finci L., et al. “Signaling mechanism of the Netrin-1 receptor DCC in axon guidance”. Progress in Biophysics and Molecular Biology3 (2015): 153-160.
12. Ranganathan PV., et al. “Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2-mediated PGE2 production”. Kidney International6 (2013): 1087-1098.
13. Ziegon L and Schlegel M. “Netrin-1: A modulator of macrophage driven acute and chronic inflammation”. International Journal of Molecular Sciences1 (2021): 275-283.
14. Ly NP., et al. “Netrin-1-inhibits-leukocyte-migration in vitro and in vivo”. Proceedings of the National Academy of Sciences of the United States of America 41 (2005): 14729-14734.
15. Mediero A., et al. “Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis”. Annals of the Rheumatic Diseases 9 (2016): 1706-1713.
16. Mediero A., et al. “Netrin-1 is a critical autocrine/paracrine factor for osteoclast differentiation”. Journal of Bone and Mineral Research 5 (2015): 837-854.
17. Kenta Maruyama., et al. “Bone-protective functions of Netrin 1 protein”. Journal of Biological Chemistry 46 (2016): 23854-23868.
18. Shouan Zhu., et al. “Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain”. Journal of Clinical Investigation 3 (2019): 1076-1093.
19. Park KW., et al. “The axonal attractant Netrin-1 is an angiogenic factor”. Proceedings of the National Academy of Sciences of the United States of America 46 (2004): 16210-16215.
20. Wilson BD., et al. “Netrins promote developmental and therapeutic angiogenesis”. Science5787 (2006): 640-644.
21. Lingyu Jiang., et al. “Role of Slit/Robo signaling pathway in bone metabolism”. International Journal of Biological Sciences 3 (2022): 1303-1312.
22. Nencini S and Ivanusic JJ. “The physiology of bone pain. How much do we really know?” Frontiers in Physiology 7 (2016): 157-163.
23. Negishi-Koga T., et al. “Suppression of bone formation by osteoclastic expression of Semaphorin 4D”. Nature Medicine 11 (2011): 1473-1480.
24. Marsick BM., et al. “Activation of ADF/cofilin mediates attractive growth cone turning toward nerve growth factor and Netrin-1”. Developmental Neurobiology 8 (2010): 565-588.
25. Smolen JS., et al. “Rheumatoid arthritis”. Lancet10055 (2016): 2023-2038.
26. Mian Xiao., et al. “The expression of Netrin-1 in the MIA-induced osteoarthritic temporomandibular joint in mice”. Scientific Reports 1 (2021): 15695.