Our longstanding interest is to study the molecular, cellular and genetic basis underlying cell function, differentiation and crosstalk in skeletal development, homeostasis, disease and repair. The skeleton, is a very dynamic tissue where the interactions between cells within bone, but also with the bone marrow, muscle and tendons are numerous and complex. Furthermore, bone communicates with, is affected by and regulates the function of distant organs, in particular the kidney and the gut in calcium and phosphate homeostasis, but also the brain. We are particularly interested in the identification and characterization of genes that regulate bone development and homeostasis in health and disease with a particular emphasis on molecular signaling pathways (parathyroid hormone signaling, WNT signaling) and the mechanisms by which they regulate these processes and can be used in treatment of various bone diseases where bone homeostasis is disturbed. These include diseases of bone fragility due to bone loss (osteoporosis, osteogenesis imperfecta for instance) or diseases in which bone mass is abnormally high (osteopetrosis, osteosclerosis for instance. We are also interested in elucidating the mechanisms involved in rare diseases of the skeleton where bone is rapidly lost or abnormally shaped during childhood (Pyle disease, MCTO, OPPG for instance). In these studies, we focus particularly on the biology of the cells that make bone, the osteoblasts, and the cells that resorb the bone matrix, the osteoclasts.

 

In this overall context, we have a particular interest in the molecular events involved in signaling from the PTH/PTHrP receptor and the Wnt signaling pathway. These pathways are among the most important during development, but also in disease situations and as therapeutic approaches. Rare human mutations gain- and loss-of- function studies in mice have clearly shown that alterations in these pathways lead to altered bone development and mass. Work from our lab, including studies on the role of various Wnt ligands (Wnt1, Wnt16) in skeletal homeostasis established that trabecular and cortical bone are differentially regulated. Our recent work on Sfrp4, a WNT signaling inhibitor, have established that loss of function mutations of SFRP4 lead to Pyle’s disease (OMIM 265900), a rare skeletal disease characterized by limb deformity and fragility fractures.

 

Our second major interest in the laboratory is to better understand the biology of one bone cell type that has been very difficult to study so far because it is deeply embedded within the mineralized bone matrix: the osteocyte. Yet, this cell type is by far the most abundant in the skeleton and, possibly one of the most abundant cell type in the entire organism. Our focus of interest is to understand the mechanisms that regulate the activity of these cells within their small “lacunae” deep inside the bone matrix. In particular, we are trying to analyze by single cell analysis their heterogeneity, the mechanisms by which they interact with the matrix, degrade and rebuild their walls. Genetic manipulations in mice and various disease or physiological models (mechanical loading/unloading, lactating mothers) are used to explore this relatively uncharted territory at the cellular and molecular levels.