Hes1: A Genetic Target for Reversing the Pathogenesis of Osteoarthritis

Research finds a potential route for targeted therapies to inhibit development and progression.

Researchers at the Spanish National Cancer Research Centre have identified a new target in osteoarthritis (OA): Hes1.

This target, which is a mediator on the Notch signaling pathways, was revealed as an important factor in OA pathogenesis and progression in a genetically engineered mouse model. The Hes1 singling pathway affects matrix metalloproteinase 13 (MMP13) expression, and A-Disintegrin-And-Metalloproteinase-with-Thrombospondin-like-Sequences-5 (ADAMTS5), both of which are known catabolic enzymes that break down cartilage matrix proteins.

Inducing Hes1 expression by adding Hes1 genes to genetically modified mice promoted both MMP13 and ADAMTS5 activation. Hes1 expression appeared to exert this effect through a calmodulin-dependent protein complex in cartilage tissues.

Further supporting the importance of Hes1 in OA development, researchers designed mice that lacked the Hes1 gene altogether (so-called Hes1-knockout mice). These mice were less likely to develop OA.

This research points to a possible foothold for research into targeted therapies that inhibit, or even reverse, the pathogenic processes involved in the development and progression of OA.

At least 1 currently available drug has activity against Hes1—the anti-inflammatory steroid drug methylprednisolone. Unfortunately drugs in this class have many other effects that may preclude use in all but the most severe cases of OA. A targeted Hes1 inhibitor, if developed, could potentially act more specifically against Hes1, resulting in fewer negative systemic side effects with equal or superior efficacy to systemic corticosteroid treatment.

Drug-mediated inhibition of pathways related to the notch signaling pathway have shown positive effects in patients with osteoarthritis. For instance, the JAK/STAT inhibitor ruxolitinib (Jakafi) has been researched for multiple disease, including arthritis. However, it is important to note that ruxolitinib is currently only indicated for treatment of certain myeloproliferative neoplasms at present.

Though the risk/benefit profile of ruxolitinib may not be sufficiently favorable to grant the drug approval for use in patients with OA (and the prohibitive cost would prevent its widespread use), the pathway of ruxolitinib is known to have downstream effects on notch signaling mediators, such as Hes1. If another drug were designed to act more specifically on Hes1, enhanced efficacy and fewer adverse events might lead to improved OA outcomes with fewer negative treatment-limiting side effects.

Assays of several drugs have been conducted by basic researchers against Hes1. These inhibitors include lindbladione (a compound found in slime molds), lycogalic acid A (a synthetic compound), nudiposide, and lyoniside. Of these drugs, lyoniside has the most favorable binding profile, suggesting the greatest potency and inhibitory capacity against Hes1 of known Hes1 inhibitors.

References

• Sugita S, Hosaka Y, Okada K, et al. Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2. Proc Natl Acad Sci U S A. 2015;112(10):3080-3085.
• National Institutes of Health. HES1 Structure. http://www.rcsb.org/pdb/images/2mh3_asr_r_500.jpg. Accessed July 2015.
• Wang W, Wang P, Li S, et al. Methylprednisolone inhibits the proliferation and affects the differentiation of rat spinal cord-derived neural progenitor cells cultured in low oxygen conditions by inhibiting HIF-1α and Hes1 in vitro. Int J Mol Med. 2014;34(3):788-795.
• Seavey MM, Dobrzanski P. The many faces of Janus kinase. Biochem Pharmacol. 2012;83(9):1136-1145.
• El-Habr EA, Levidou G, Trigka EA, et al. Complex interactions between the components of the PI3K/AKT/mTOR pathway, and with components of MAPK, JAK/STAT and Notch-1 pathways, indicate their involvement in meningioma development. Virchows Arch. 2014;465(4):473-485.
• PubChem Database. https://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?geneid=15205. Accessed July 2015.
• Arai MA, Masada A, Ohtsuka T, Kageyama R, Ishibashi M. The first Hes1 dimer inhibitors from natural products. Bioorg Med Chem Lett. 2009;19(19):5778-5781.
• Oakdale JS, Boger DL. Total synthesis of lycogarubin C and lycogalic acid. Org Lett. 2010;12(5):1132-1134.