Skeletal Physiopathology and Joint Regenerative Medicine

This team is composed of 28 people (22.5 full-time equivalent) including 8 senior researchers with Research Supervisor Qualifications (HDR). The team is headed by J. Guicheux and L. Beck as deputy head.

The STEP team is a translational and transdiciplinary team that focuses on the integrated physiology and aging of the skeleton from their basic aspects (phosphate homeostasis, mineralization, senescence, autophagy, Theme 1) to more applied aspects (osteoarthritis, ectopic calcification). The STEP team also studies the fundamental processes of stem cell fate and differentiation (Theme 2) during development of cartilage and intervertebral disc. The team also supports the development of bio-inspired hydrogels (Theme 3) and protocol to exploit the properties of mesenchymal or pluripotent stem cells for the regenerative medicine of cartilages (osteoarthritis, disc degeneration - Theme 4).

Theme 1 - Integrative skeletal physiology and aging

Leader: L. Beck

This theme involves 2 senior scientists (L. Beck CR1 Inserm, S. Beck-Cormier CR1 CNRS),  2 University/Hospital Professors (L. Figueres MCU PH, Laure Merametdjian MCU Associée) and 1 PhD student (G. Frangi).

Our research aims at characterizing original mechanisms of physiological and pathological mineralization. In this context, our work is focused for the most part on the role of the PiT1 and PiT2 proteins in 1) the angiogenesis-osteogenesis coupling by modulating the secretion of VEGF-A, and the action of BMP2 and 4 through the regulation of MGP; 2) the adipogenesis-osteogenesis coupling by modulating the Bone Marrow Mesenchymal Stem cells fate towards either lineage; 3) the mechanisms whereby the variation of extracellular Pi leads to the appropriate secretion of the phosphaturic hormone FGF23 and 4) the mineralization of the skeleton by modulating the action of FLH2 and the SIBLINGs proteins.

Theme 2 - Stem cells and axial skeleton development

Stem Cells and Axial Skeleton Development

Leader: A. Camus

This theme involves 1 senior scientist (A. Camus-CR1 CNRS), 1 PhD candidate starting in October 2017 and
1 technical staff (A. Henry Ass-Engineer)

An important question in embryology and stem cell biology is when and how precursor cells are specified and differentiate. Today, our understanding of intervertebral disc (IVD) morphogenesis is far from complete. We also have a limited knowledge of the controlling signalling pathways, transcriptional regulators and morphogens implicated in disc differentiation at each developmental stage and during growth and maturation. A more in-depth understanding of the cellular and molecular mechanisms of intervertebral disc development is however a prerequisite to properly address the biological causes of disc degeneration and develop innovative regenerative strategies for the IVD.

Theme 3 - Hydrogel and joint microenvironment

Hydrogels
Leader: C. Le Visage

This theme involves 1 senior scientist (C. Le Visage DR2 Inserm), 3 University/Hospital Professors (J. Clouet (MCU-PH), G. Grimandi (PU-PH), A. Chabaud (MCU)), currently 3 PhD students (L. Frapin, M. Gluais, A. Smith) and 1 technical staff (C. Chédeville).

To reproduce the complex 3 dimensional (3D) microenvironment experienced by cells in vivo, we have selected hydrogels, i.e complex networks of hydrophilic crosslinked polymers, for their similarity with the extracellular matrix of tissues. Our research is focused on natural, bioresorbable and non-immunogenic polysaccharides that are already commercialized for medical applications. Alginate (seaweed), a widely used biomaterial, is rapidly destabilized in a physiological environment. Thus we investigate hydroxypropylmethylcellulose (cotton) and pullulan (yeast fermentation) to design innovative hydrogels with tunable porosity and network diffusion parameters. Using various fabrication techniques, we develop chemically cross-linked hydrogels with complex architectures, tunable viscoelasticity and desired ability to mediate cellular activities through the spatial and temporal presentation of biological cues. We investigate hydrogels as i) tools for stem cell-based organogenesis (collaboration with Theme 2) and ii) carriers of cells or bioactive molecules for bio-inspired delivery strategies in cartilage regeneration that will be assessed in Theme 4.


Theme 4 - Translational research in joint regeneration

Leader: J. Guicheux

This theme involves 1 senior scientist (J. Guicheux DR2 Inserm), 1 University associate Professor (C. Vinatier (associate Professor), 3 University/Hospital Professors (Y. Maugars (PU-PH), O. Geffroy (PR Oniris), Marion Fusellier (MC ONIRIS)), 1 post doctoral fellow (C. Boyer), 2 PhD students (B. Bodic, A. Fouasson-Chailloux), 1 technical staff (M. Dutilleul Ass-engineer).

Joint cartilaginous tissues, notably articular cartilage (AC) and intervertebral disc (IVD), have very low self-repair capacity making their age-associated degeneration irreversible. Recently, facing the absence of efficient treatment for OA and IVD degeneration, it has been proposed to exploit the biological properties of stem cells notably those related to their ability (i) to repair or regenerate skeletal tissues, (ii) to modulate immune cell functions (iii) to secrete biological factors involved in the control of inflammation. In this context, the use of scaffolds and biomimetic materials able to support transplantation, survival and engraftment of stem cells is considered with interests notably for the repair of joint tissues. The last decade, intense research on OA and IVD degeneration and physiopathology has led to the discoveries of novel biological cascades (TGF-SMAD, Zinc-Zip8 axis, HIF-dependent signaling, WNT/Beta-Catenin, autophagy/senescence, geronic factors..) playing key roles in cartilage homeostasis and degeneration. Among these cascades, we are particularly interested in the regulation of the autophagy/senescence balance and the role of specific anti-geronic factors during joint aging and osteoarthritis. Whether we will be able to translate these recent discoveries into successful treatments for OA and IVD degeneration remain a challenge we would like to tackle in the near future.