Regulating recruitment of osteoclast progenitors to bone matrix to control osteoporosis

Osteoporosis is the most common age-related bone disease which affects hundreds of millions of individuals worldwide. It is estimated that one in three women and one in five men aged over 50 suffer from osteoporotic bone fractures.

Osteoporosis is caused by excessive activity of bone resorbing cells, while activity of bone-forming cells is reduced. In healthy individuals, a balanced activity of these two cell types allows constant bone turnover to maintain healthy and strong bones.

In osteoporosis, disproportionate bone resorption leads to low bone mineral density and consequently weak and fracture-prone bones. When new bone formation is unable to catch up with bone loss, bone eventually weakens, and becomes more prone to fractures.

Most current osteoporosis therapies include the use of bisphosphonates, which block the activity of bone resorbing cells, and thus prevent excessive bone resorption. However, prolonged treatment with these drugs eliminates the necessary bone turn-over leading to increased fracture risk and other unwanted side effects. Therefore, there is an urgent need to develop new strategies that overcome the limitations of current treatments.

There are now new progresses in this area. The results have been published in the journal PNAS.

Using genetic analysis in a small laboratory fish model, the Japanese medaka (Oryzias latipes), the research team identified a small protein, the chemokine CXCL9, that, under osteoporotic conditions, diffuses towards reservoirs that hold bone resorbing cell precursors. These precursors produce a receptor, CXCR3, on their cell surface. Upon activation by CXCL9, the precursors are mobilised and migrate long distances in a highly directed fashion towards the bone matrix, where they start resorbing bone.

Both CXCL9 and its receptor CXCR3 have long been known to modulate the migration of immune cells to inflammation sites, for example in psoriasis and rheumatoid arthritis. There are several chemical inhibitors blocking CXCR3 activity that have had little success in clinical tests for the treatment of psoriasis. The research team showed that these inhibitors are highly effective in blocking bone resorbing cells' recruitment and protecting bone from osteoporotic insult.

The conclusion of the authors: "Our studies provided new avenues to osteoporosis therapy. The new strategy allows a fine-tuned modulation of osteoclast numbers that are recruited to bone matrix rather than a widespread blockage of osteoclast activity as in traditional therapies. This has major advantages as excessive bone resorption can be prevented in a targeted manner but normal bone turn-over will still continue. This offers potential to avoid increased fracture risks in osteoporosis patients and to maintain healthy bone for improved quality of life."

https://www.uni-wuerzburg.de/aktuelles/pressemitteilungen/single/news/neue-strategie-gegen-osteoporose/

https://www.pnas.org/content/early/2020/07/24/2006093117

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fcxcl9l-and-cxcr3-2&filter=22