H2S in Degenerative and Inflammatory Joint Diseases

Osteoarthritis (OA) is one of the most common degenerative joint diseases, which very often affects older people, and in which inflammatory processes are involved in the development and progression of the disease. Until today, no cure is possible. Non-steroidal anti-inflammatory drugs (NSAIDs) like Diclofenac and Ibuprofen, both inhibiting the synthesis of prostaglandins by inhibiting cyclooxygenase (COX)-1 and COX-2, are among the few available drug treatment options today. However, highly effective drugs are still lacking. 

It is well known that hydrogen sulfide (H₂S) is a potent anti-oxidant and shows anti-inflammatory effects as published multiple times from our group. In this project, we aim to design and synthesize so called “hybrid molecules” consisting of a commercially available NSAID (Naproxen or Ibuprofen, etc.) and a H₂S-releasing domain (P*) developed by E Galardon (University Paris Descartes). These molecules will be termed as “Pen-Naprox” and “Pen-Ibu”. Due to the fact that these hybrid molecules are able to release H₂S, we expect that these compounds have a greater anti-inflammatory and anti-oxidative potential than the parent drugs Naproxen and Ibuprofen, respectively.

Both bone formation by osteoblasts and bone resorption by osteoclasts constitute bone reconstruction homeostasis. However, an imbalance between bone formation and bone resorption will disturb bone homeostasis, resulting in various diseases.

Experiments, performed with bone marrow derived monocytes/macrophages from mice (Medical University of Vienna, group of G Steiner), demonstrated that P* significantly inhibited RANKL-induced osteoclast differentiation in a dose-dependent manner. Moreover, data show that in a K/BxN serum transfer arthritis model the number of osteoclasts, cartilage loss as well as inflammation area, respectively, were significantly reduced by the classic H₂S donor sodium hydrogen sulfide (NaHS) (S Bauer/D Sieghart).

Currently, the effects of Pen-Naprox and Pen-Ibu and a H₂S-releasing bisphosphonate on osteoclast differentiation are investigated in vitro and in vivo in cooperation with the group of NA Lopez (Medical University of Graz), T Pap (University of Muenster, Germany) and J Grillari (LBI for Traumatology, Vienna).