Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes

Minguzzi, Manuela; Panichi, Veronica; D’Adamo, Stefania; Cetrullo, Silvia; Cattini, Luca; Flamigni, Flavio; Mariani, Erminia; Borzì, Rosa Maria

doi:10.3390/ijms222112012

Open AccessArticle

Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes

by

Manuela Minguzzi

^1,†,

Veronica Panichi

^2,†,

Stefania D’Adamo

¹,

Silvia Cetrullo

²

,

Luca Cattini

³,

Flavio Flamigni

²

,

Erminia Mariani

^1,3 and

Rosa Maria Borzì

^3,*

¹

Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, 40138 Bologna, Italy

²

Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, 40138 Bologna, Italy

³

Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2021, 22(21), 12012; https://doi.org/10.3390/ijms222112012

Submission received: 14 July 2021 / Revised: 29 October 2021 / Accepted: 30 October 2021 / Published: 5 November 2021

(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)

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Abstract

Notch signaling has been identified as a critical regulator of cartilage development and homeostasis. Its pivotal role was established by both several joint specific Notch signaling loss of function mouse models and transient or sustained overexpression. NOTCH1 is the most abundantly expressed NOTCH receptors in normal cartilage and its expression increases in osteoarthritis (OA), when chondrocytes exit from their healthy “maturation arrested state” and resume their natural route of proliferation, hypertrophy, and terminal differentiation. The latter are hallmarks of OA that are easily evaluated in vitro in 2-D or 3-D culture models. The aim of our study was to investigate the effect of NOTCH1 knockdown on proliferation (cell count and Picogreen mediated DNA quantification), cell cycle (flow cytometry), hypertrophy (gene and protein expression of key markers such as RUNX2 and MMP-13), and terminal differentiation (viability measured in 3-D cultures by luminescence assay) of human OA chondrocytes. NOTCH1 silencing of OA chondrocytes yielded a healthier phenotype in both 2-D (reduced proliferation) and 3-D with evidence of decreased hypertrophy (reduced expression of RUNX2 and MMP-13) and terminal differentiation (increased viability). This demonstrates that NOTCH1 is a convenient therapeutic target to attenuate OA progression.

Keywords: osteoarthritis; chondrocytes; hypertrophy; remodeling; angiogenesis

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MDPI and ACS Style

Minguzzi, M.; Panichi, V.; D’Adamo, S.; Cetrullo, S.; Cattini, L.; Flamigni, F.; Mariani, E.; Borzì, R.M. Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes. Int. J. Mol. Sci. 2021, 22, 12012. https://doi.org/10.3390/ijms222112012

AMA Style

Minguzzi M, Panichi V, D’Adamo S, Cetrullo S, Cattini L, Flamigni F, Mariani E, Borzì RM. Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes. International Journal of Molecular Sciences. 2021; 22(21):12012. https://doi.org/10.3390/ijms222112012

Chicago/Turabian Style

Minguzzi, Manuela, Veronica Panichi, Stefania D’Adamo, Silvia Cetrullo, Luca Cattini, Flavio Flamigni, Erminia Mariani, and Rosa Maria Borzì. 2021. "Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes" International Journal of Molecular Sciences 22, no. 21: 12012. https://doi.org/10.3390/ijms222112012

APA Style

Minguzzi, M., Panichi, V., D’Adamo, S., Cetrullo, S., Cattini, L., Flamigni, F., Mariani, E., & Borzì, R. M. (2021). Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes. International Journal of Molecular Sciences, 22(21), 12012. https://doi.org/10.3390/ijms222112012

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Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes

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