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Contact

Olivier Chassande

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Contact

Linkedin biotis-bordeaux

Secretary Email

33 (0)5 57 57 14 88

Bioingénierie Tissulaire (BioTis)       

Physical Address:

Batiment BBS (Bordeaux Biologie Santé), 5e étage

2, rue du Dr Hoffmann Martinot,

33000, Bordeaux, France

Mailing Address:

Université de Bordeaux, Campus Carreire

146, rue Léo Saignat, Case 84,

33076, Bordeaux Cedex, France

Modeling Sensory Neuron-Chondrocyte Interactions in Osteoarthritis: An iPSC-Derived Microfluidic Platform for Drug Discovery

Abstract

Reference

Line Kawtharany

Project Leader

In OA, neuroplastic changes such as nerve sprouting and altered innervation patterns contribute to chronic pain and joint dysfunction (2). Additionally, the hypersensitivity of sensory neurons (SN) in OA leads to increased pain during normal joint movements, which is termed “hyperalgesia” (3). The interaction between SN and cartilage is bidirectional. Inflammatory and mechanical stimulus in OA joints activate SN. SN can also release neuropeptides that promote cartilage degradation. Notably, increased levels of neuropeptides like calcitonin gene-related peptide (CGRP) and substance P (SP) in OA joints correlate with disease severity (4). These neuropeptides not only mediate joint pain but also indirectly induce cartilage degradation by promoting the release of pro-inflammatory factors (5). Conversely, cartilage-derived factors regulate SN plasticity. CC in OA conditions produce nerve growth factor (NGF) (6), brain-derived neurotrophic factor (BDNF) (7), prostaglandin 2 (PGE2) (8) and nitric oxide (NO) (9), which influence axonal sprouting and SN sensitization associated with OA pain. Our project aims at 1) setting up an original in vitro model of human SN, derived from induced pluripotent stem cells (iPSCs) (10) and grown on microfluidic chips to 2)explore the interactions between SN and chondrocytes and to 3) screen candidate drugs for the treatment of OA-induced pain and SN-mediated cartilage degradation.                      

▷Arden, N. K., Perry, T. A., Bannuru, R. R., Bruyère, O., Cooper, C., Haugen, I. K., ... & Reginster, J. Y. (2021) Nature Reviews Rheumatology, 17(1), 59-66.

▷Suri, S. et al. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Annals of the rheumatic diseases 66, 1423-1428 (2007).

▷Malfait, A.-M., Miller, R. E. & Miller, R. J. Basic mechanisms of pain in osteoarthritis: experimental observations and new perspectives. Rheumatic Disease Clinics 47, 165-180 (2021).

▷Wang, H. et al. Increasing expression of substance P and calcitonin gene-related peptide in synovial tissue and fluid contribute to the progress of arthritis in developmental dysplasia of the hip. Arthritis Research & Therapy 17, 1-12 (2015).

▷Lotz, M., Vaughan, J. H. & Carson, D. A. Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 241, 1218-1221 (1988).

▷Pecchi, E. et al. Induction of nerve growth factor expression and release by mechanical and inflammatory stimuli in chondrocytes: possible involvement in osteoarthritis pain. Arthritis research & therapy 16, 1-11 (2014).

▷Forsgren, S. New data favouring that neurotrophins are of importance in arthritis. Arthritis Research & Therapy 11, 122 (2009).

▷Shimpo, H. et al. Regulation of prostaglandin E(2) synthesis in cells derived from chondrocytes of patients with osteoarthritis. J Orthop Sci 14, 611-617 (2009).

▷Abramson, S. B. Nitric oxide in inflammation and pain associated with osteoarthritis. Arthritis Research & Therapy 10, S2 (2008).

▷Muller, Q. et al. Development of an innervated tissue-engineered skin with human sensory neurons and Schwann cells differentiated from iPS cells. Acta Biomater 82, 93-101 (2018).

Collaborator

Osteoarthritis is a degenerative, inflammatory disease which involves articular cartilage degradation and pain. Osteoarthritis (OA) is the most common debilitating joint disorder worldwide, clinically affecting patients chiefly by joint pain, functional limitations, and a considerably reduced quality of life. OA is chiefly characterised pathologically by loss of articular cartilage, remodelling of the subchondral bone, associated inflammation besides affecting all other tissues constituting a joint (1).SN are integral to the pathophysiology of OA, influencing both pain perception and joint homeostasis.