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30

Main research area


Osteoarthritis is the most common disease in the elderly. Indeed, 65% of people over 60 years of age have osteoarthritis. Despite the high prevalence of osteoarthritis, its pathophysiology is not clearly established, especially since osteoarthritis is a multifactorial disease. The initial definition of osteoarthritis as the degeneration of cartilage with cyclic inflammatory phases under the dependence of the synovial membrane (the membrane surrounding the joint) is somewhat simplistic. Indeed, it is now accepted that bone and in particular subchondral bone (bone under the cartilage) plays a role in the arthritic process.

One of the characteristics of osteoarthritis is an attempt to repair cartilage by chondrocytes (cartilage cells), but this repair fails, particularly under the influence of factors secreted by the synovial membrane and subchondral bone. These factors can concurrently increase cartilage degradation and decrease repair, but also cause chondrocytes to dedifferentiate and return to expressing genes normally found in growth plates (conjugation cartilage) or during bone repair (endochondral ossification). Among the different re-expressed genes are those of collagenase-3 (MMP-13) and galectin-3.

            One of the growth factors found in greater quantity in osteoarthritic cartilage is hepatocyte growth factor (HGF). However, its synthesis is restricted to osteoblasts (bone cells), which suggests a paracrine role of this factor. In addition, in human chondrocytes, this HGF stimulates the production of collagenase-3, which is involved in cartilage remodeling and destruction, via the mitogen-activated protein kinases (MAPK) pathway.

During their de-differentiation, osteoarthritic chondrocytes also express and produce larger quantities of galectin-3, which is a lectin with different functions depending on its intra- or extracellular distribution. Although osteoarthritic chondrocytes produce more galectin-3, they secrete only small amounts. However, its intracellular presence is beneficial for chondrocytes since animals deficient in galectin-3 develop more osteoarthritis than non-mutated animals. In addition, using in vitro experiments, galectin-3 has a protective role against chondrocyte death. These results highlight the role of galectin-3 in cartilage homeostasis. However, animals deficient in galectin-3 do not have subchondral bone abnormalities except in the induction of osteoarthritis by intra-articular injection of mono-iodoacetate. These results show that galectin-3 does not appear to be essential for bone homeostasis, but when bone is subjected to metabolic stress, the absence of intracellular galectin-3 is harmful.

In contrast, galectin-3 can be secreted by the synovial membrane during inflammatory phases. During the latter, the synovial membrane generates a specific structure called pannus that envelops the cartilage and bone. Galectin-3 secretion can therefore directly reach chondrocytes and osteoblasts. Using chondrocytes, galectin-3 induces the expression of two major enzymes involved in the degradation of proteoglycans, one of the major components of the cartilage matrix. Galectin-3 also stimulates the expression of type X collagen, another cartilage compound normally expressed in the growth plate. Incubation of arthrosic osteoblasts in the presence of galectin-3 decreases the expression of osteocalcin, which is a marker of terminal osteoblast differentiation. According to literature,a truncated form of galectin-3, capable of binding to galectin-3 ligands but without activating a cellular signal, does not have this effect. Several strategies in order to produce a Trc-gal-3, devoid of biological activities was developed in the lab. Unfortunately, all of them presented biological effects on osteoarthritic chondrocytes. Among the Trc-gal-3 forms developed, one was selected because it had enough affinity for lactose and a great solubility. Thanks to theses properties, this form is used to generate a new method of purification of recombinant proteins.


Article dans une revue23 documents

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Communication dans un congrès3 documents

  • Alexandre Kriznik, Melissa Yelehe-Okouma, Christophe Charron, Hortense Mazon, Hélène Le Cordier, et al.. Efficient new lectin-based affinity tag allowing simple, safe and low-cost recombinant protein purification. The 14th International Symposium on BioChromatography and Nanoseparations, May 2018, Bordeaux, France. 2018. 〈hal-01719814〉
  • J. Hablot, M. Koufany, P. Reboul, J.-Y. Jouzeau, D. Moulin. FRI0017 Pharmacological Blockade of CCR3 Reduces Collagen-Induced Arthritis Severity. Annual European Congress of Rheumatology (EULAR), 2016, Londres, United Kingdom. ANNALS OF THE RHEUMATIC DISEASES, 75 (Suppl 2), pp.431.3 - 432, 2016, 〈10.1136/annrheumdis-2016-eular.4069〉. 〈hal-01706984〉
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Chapitre d'ouvrage3 documents

  • Elie Abed, Pascal Reboul, Daniel Lajeunesse. Sirtuins as markers of bone disease: a focus on osteoarthritis and osteoporosis.. Professor Victor R. Preedy. Biomarkers in Disease: Methods, Discoveries and Applications, Springer publisher, pp.154-175, 2017. 〈hal-01709897〉
  • Johanne Martel-Pelletier, Daniel Lajeunesse, Pascal Reboul, Jean-Pierre Pelletier. The role of subchondral bone in osteoarthritis. Leena Sharma & Francis Berenbaum. Osteoarthritis, first edition, Mosby Elsevier publisher, pp.15-32, 2007. 〈hal-01709917〉
  • Daniel Lajeunesse, P. Reboul. The role of bone in the development of osteoarthritis.. F Bronner and MC Farach-Carson. Bone and Osteoarthritis, 4, pp.19-39, 2007, Topics in Bone Biology. 〈hal-01710478〉

Brevet1 document

  • Alexandre Kriznik, Pascal Reboul, Melissa Yelehe-Okouma. Method for the affinity purification of recombinant proteins based on the lectin affinity of the CRD of a Galectin. France, N° de brevet: WO2017194888. 2017. 〈hal-01872013〉