Excessive osteoclasts activation can lead to osteolysis, which is a key feature in several inflammatory pathologies such as rheumatoid arthritis and various bone diseases including osteoporosis, periodontitis, Paget’s disease and osteolytic tumors [35, 36] Current therapies are targeting either osteoclasts (i.e. antiresorptive bisphosphonates or Cathepsin K inhibitors) or osteoblasts (i.e. anabolic parathyroid hormone) but are not spared of sometimes severe side effects (e.g. renal toxicity and osteonecrosis). Here, CTSK is linked to osteonecrosis.