Bone degradation by osteoclasts

Osteoclast fusion and function in health and disease

One of our projects consists in deciphering the cellular and molecular mechanisms leading to the formation and function of human osteoclasts. The bone skeleton is subjected to continuous remodeling, which mainly relies on the concerted and balance action of bone-forming osteoblasts and bone-resorbing osteoclasts. With age and various pathological conditions, osteoclast activity takes over that of osteoblasts, driving progressive reduction of bone mass and osteoporosis. In France, the number of people aged 50+ with osteoporosis is approximately 3.5 million and, by 2050, the incidence of hip fracture is projected to increase by 300% in elderly people (International Osteoporosis Foundation). In this context, it is crucial to better understand how osteoclasts are generated and remodel bone, in particular in ageing conditions.

Osteoclasts are multinucleated cells of myeloid origin responsible for the degradation of bone and unique in this function. When mature osteoclasts resorb bone, they form a sealing zone, which is a bone-anchored adhesion structure. The sealing zone demarcates the area of bone resorption from the rest of the environment, and we recently described it at the nanoscale as a complex assembly of podosomes [1]. The main objective is now to identify new molecular actors in fusion/function of human osteoclasts and validate their role in vivo in mice. Actually, we are working on two candidates: the ezrin/radixin/moesin (ERM) protein family and the integrin activation regulators Riam and Lamelipodin (collaboration, F Lagarrigue, IPBS, Toulouse). With the LAAS (in collaboration with Laurent Malaquin), we are also designing approaches based on microfluidics and microfabrication to facilitate the quantification of cell-to-cell fusion and bone resorption processes. We will also determine whether the age of monocyte donors affect the efficiency of the fusion process and the regulation of the main identified actors in osteoclast fusion and/or function.

Unrevealing the mechanisms of osteoclast formation and function, and their modification with age are crucial steps to determine novel therapeutic approaches dedicated to osteoclast-linked pathologic settings, including osteoporosis.

1. Portes, M., et al. Nanoscale architecture and coordination of actin cores within the sealing zone of human osteoclasts. Elife, 2022. 11