Cartilaginous Tissues Physiopathology and Therapeutic.
Manager: Hervé KEMPF
Cartilage is composed of a single cell type: the chondrocyte. Depending on the location of the cartilage and its stage of development, chondrocytes can exhibit distinct phenotypes. Alteration of these phenotypes is responsible for numerous diseases, ranging from rare genetic disorders such as skeletal dysplasias to prevalent, chronic, and debilitating joint diseases such as osteoarthritis. Studying the players and mechanisms behind these alterations is therefore crucial for understanding the pathophysiology of these diseases and identifying potential therapeutic targets and solutions. Our strategic choices rely on a range of in vitro, ex vivo, and in vivo skills and approaches.
The team’s project is structured around three research axes aimed at studying the respective contributions of anti-mineralizing factors (inorganic pyrophosphate or PPi, Matrix Gla Protein or MGP), metabolic factors (hyperglycemia, hyperlipidemia), and lipid nanoparticles to phenotypic changes in chondrocytes across different cartilaginous tissues and pathophysiological conditions, with the goal of contributing to the development of curative treatments for cartilage diseases.
Keywords – Chondrocytes; Cartilage; Calcification; Metabolism; Pyrophosphate (PPi); Matrix Gla Protein (MGP); Joint; Trachea; Growth Plate; Nanoliposomes; Mouse Models; Metabolic Osteoarthritis; Traumatic Osteoarthritis; Rare Disease; Keutel Syndrome; Inflammation; Adipose Tissue; Hoffa’s Fat Pad; Pathophysiology; Therapeutic Targets; Phenotype; Extracellular Vesicles; Progenitor Cells.
Research axis
Axis 1 – Calcification Inhibitors and Cartilage – ICCAR
Our previous work has highlighted the major role of calcification inhibitors in maintaining and/or altering chondrocyte phenotype. We demonstrated that in the context of osteoarthritis, PPi protects articular chondrocytes from inflammatory signals, and that during postnatal development, MGP enables growth plate and tracheal chondrocytes to differentiate properly. Conversely, any disruption in the expression or activity of these two mineralization inhibitors results in phenotypic changes in articular, growth plate, and/or tracheal cartilage chondrocytes.
Our current work aims to:
- clarify the role of PPi and investigate that of MGP in phenotype changes of articular chondrocytes during osteoarthritis,
- identify and characterize the molecular and cellular mechanisms underlying phenotypic changes observed following MGP deficiency in growth plate and tracheal cartilage.
Axis 2 – Metabolic Disorders and Articular Cartilage – METACARP
Osteoarthritis is a degenerative joint disease where cartilage erosion is the primary lesion. It manifests clinically as functional impairment of the affected joints, often accompanied by pain. Recently, our research has focused on the contribution of metabolic syndrome to joint damage. It is now well established that beyond obesity, metabolic imbalances related to cardiovascular disorders can be risk factors for osteoarthritis. The comorbidities associated with obesity (e.g., high cardiovascular risk, hypertension, type 2 diabetes, hyperglycemia, dyslipidemia) define this syndrome, which is not a disease per se but rather a phenotype characterized by metabolic and inflammatory disruptions.
We have shown, using the obese SHHF rat model with metabolic syndrome (MetS), that :
- their metabolic disturbances lead to a severe spontaneous osteoarthritis phenotype, and
- the onset of degenerative changes can be prevented by chronic preventive treatment with eplerenone, a mineralocorticoid receptor (MR) antagonist.
Building on this data, our ongoing work aims to:
- characterize the curative properties of eplerenone in the MetS-related osteoarthritis model (SHHF rat) and assess its therapeutic potential in other experimental models of osteoarthritis not related to MetS,
- determine whether the MR plays a role in chondrocyte phenotype changes occurring during osteoarthritis,
- define the individual and combined effects of cardiometabolic factors associated with MetS on the chondrocyte phenotype.
Axis 3 – Extracellular Vesicles and mimicries in Diseases and Therapeutics – EViDanT
To date, there are no pharmacological treatments capable of regenerating articular cartilage and there is a highly unmet medical need for disease-modifying therapies. The EViDant group aims to produce therapeutic nanovectors of natural origin, such as extracellular vesicles secreted by cells, or of synthetic origin, such as nanoliposomes, to adopt strategies of acellular therapy intended to create a curative treatment for osteoarthritis to restore chondrocyte phenotype and regenerate articular cartilage. Extracellular vesicles produced under pathological conditions could also be used to decipher the impact of intercellular communication on the various mechanisms of cartilage diseases. Extracellular vesicles produced under pathological conditions may also be used to decipher how intercellular communication impacts disease mechanisms in cartilage disorders.
Team’s members
Main publications
Partnership and funding
