Fibrosis
Targeting Fibrosis in Osteoarthritis (OA) to Improve Patient Outcomes
Fibrosis has been increasingly well described in OA tissues, such as cartilage and synovial membrane. Fibrosis is defined as an unresolved wound healing process. Excessive deposition of extracellular matrix components and cell proliferation lead to impaired tissue function. It contributes to joint pain, stiffness and functional limitations. Therefore, targeting fibrosis appears essential to slow down disease progression and improve patient well-being.
Our Focus on Cartilage Fibrosis
Our research has recently focused on fibrosis in OA cartilage and, more specifically, on phenotypic changes in chondrocytes, the only cell type in cartilage. Isolated from their matrix, chondrocytes can spontaneously dedifferentiate into fibrochondrocytes that produce fibroblastic type I and III collagens and the pro-fibrotic protein a-SMA, instead of type II collagen. It is increasingly believed that chondrocytes acquire a “dedifferentiated-like” phenotype that may transdifferentiate into chondro-myo-fibroblasts, inducing fibrosis and contributing to OA progression1.
CEMIP: A Key Player in Fibrosis and Inflammation
We have identified the protein CEMIP (Cell-Migration Inducing Protein) as a key regulator of chondrocyte proliferation and their transdifferentiation into "chondro-myo-fibroblasts"2. Our findings suggest that CEMIP promotes fibrosis by driving TGF-β signaling toward its pro-fibrotic pathway. Additionally, CEMIP expression is elevated in human inflamed synovial membranes, where it also regulates inflammation3. It induces fibroblast dedifferentiation and fibrotic marker expression while increasing cell proliferation and synovial hyperplasia.
CEMIP : A New Therapeutic Target
Interestingly, our studies have shown that anti-fibrotic drugs can reduce CEMIP expression in fibroblast-like synoviocytes. These findings highlight the central role of CEMIP in the development of fibrosis in OA and underscore its potential as a promising therapeutic target for slowing down OA progression and improving patient outcomes.
Exploring Integrins as New Diagnostic and Therapeutic Pathways
In parallel, we continue to investigate integrin expression and regulation in OA tissues. First, we observed, in vivo, 18F-PRGD2 fixation by coxofemoral spacing and peridiscal lumbar osteophytes in OA patients undergoing PET/SCAN imaging for oncological purposes4. We then identified αVβ5, αVβ3 and αVβ6 integrins as specific receptors for PRGD2 tracer5. Expression of these integrins was also increased in specific OA zones such as human OA cartilage compared to non-OA cartilage and within osteophytes, a small abnormal bony outgrowth in OA joints. Furthermore, the increase of integrin subunit expression (except for β6) was also observed in vitro during chondrocyte dedifferentiation, but also under profibrotic and pro-inflammatory stimuli as well as osteogenic differentiation. We also found that αVβ6 integrin expression correlated with the profibrotic marker α-SMA in human synovial membrane6. Finally, we observed that the vitronectin fragment (amino acids 381-397) could prevent TGF-β1 activation by interacting with αVβ6 in human FLS and increase the expression of α-SMA. Collectively, these data highlight the important role of integrins in the induction of fibrosis in OA, but also as a potential diagnostic tool.
References
Chondrocyte dedifferentiation and osteoarthritis
Charlier E, Deroyer C, Malaise O, Ciregia F, Neuville S, Plener Z, Malaise M and de Seny D
Biochem Pharmacol. 2019, 165:66-78.
CEMIP (KIAA1199) induces a fibrosis-like process in osteoarthritic chondrocytes
Deroyer C, Charlier E, Neuville S, Malaise O, Gillet P, Kurth W, Chariot A, Malaise M and de Seny D
Cell Death and Disease, 2019, 10(2):103.
Deroyer C, Poulet C, Paulissen G, Ciregia F, Malaise O, Plener Z, Cobraiville G, Daniel C, Gillet P, Malaise MG, de Seny D
Cellular and Molecular Life Sciences, 2022, 79:260.
¹⁸F-FPRGD₂ PET/CT imaging of musculoskeletal disorders
Withofs N, Charlier E, Simoni P, Alvarez-Miezentseva V, Mievis F, Giacomelli F, Mella C, Gambhir SS, Malaise O, de Seny D, Malaise M, Hustinx R.
Ann Nucl Med. 2015, 29:839-47.
Charlier E, Deroyer C, Neuville S, Plener Z, Malaise O, Ciregia F, Gillet P, Reuter G, Salvé M, Withofs N, Hustinx R, de Seny D, Malaise MG.
Bone Res. 2020, 8:35.
Ciregia F, Deroyer C, Cobraiville G, Plener Z, Malaise O, Gillet P, Fillet M, Malaise MG, de Seny D
Experimental & Molecular Medicine 2021, 53:210-222.
