Targeting TGF-β signaling, oxidative stress, and cellular senescence rescues osteoporosis in gerodermia osteodysplastica

W L Chan; C H Bucher; J Goldes; A C Ma; M Steiner; B M Willie; S Mundlos; U Kornak

doi:10.1111/acel.14322

Targeting TGF-β signaling, oxidative stress, and cellular senescence rescues osteoporosis in gerodermia osteodysplastica

Aging Cell. 2024 Sep 5:e14322. doi: 10.1111/acel.14322. Online ahead of print.

Authors

W L Chan^{1

2

3

4}, C H Bucher^{3

4

5}, J Goldes¹, A C Ma⁶, M Steiner¹, B M Willie^{7

8

9}, S Mundlos^{1

2}, U Kornak^{1

10}

Affiliations

¹ Institut für Medizinische Genetik Und Humangenetik, Charité-Universitätsmedizin Berlin, Berlin, Germany.
² Max-Planck-Institut für Molekulare Genetik, FG Development & Disease, Berlin, Germany.
³ BIH Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴ Julius Wolff Institute of Biomechanics and Musculoskeletal Regeneration, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁵ Berlin-Brandenburg School for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁶ Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong, China.
⁷ Research Centre, Shriners Hospital for Children-Canada, Montreal, Quebec, Canada.
⁸ Department of Pediatric Surgery, McGill University, Montreal, Quebec, Canada.
⁹ Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Quebec, Canada.
¹⁰ Institut für Humangenetik, Universitätsmedizin Göttingen, Göttingen, Germany.

PMID: 39234801
DOI: 10.1111/acel.14322

Abstract

GORAB is a key regulator of Golgi vesicle transport and protein glycanation. Loss of GORAB function in gerodermia osteodysplastica (GO) causes shortening of glycosaminoglycan chains, leading to extracellular matrix disorganization that results in wrinkled skin, osteoporosis and elevated TGF-β signaling. In this study, we investigated the role of TGF-β-signaling, oxidative stress, and resulting cellular senescence in the osteoporosis phenotype of GO. Treatment of Gorab^Prx1 conditional knockouts with the TGF-β neutralizing antibody 1D11 rescued the trabecular bone loss, indicating that TGF-β overactivation causes osteoporosis in GO. Using an inducible knockout system, we demonstrated that TGF-β dysregulation was not a cell-intrinsic effect of GORAB inactivation, but a consequence of a disorganized extracellular matrix. Enhanced TGF-β signaling caused elevated Nox4 expression in Gorab^Prx1 mutants and in GO patients' fibroblasts, resulting in overproduction of mitochondrial superoxide. The resulting oxidative stress was detected in GORAB null cells and also in wildtype bystander cells. The same effect was observed in zebrafish after TALEN-mediated gorab inactivation, indicating that the pathway is evolutionarily conserved. Treating Gorab^Prx1 mutants with the antioxidant N-acetylcysteine ameliorated the osteoporosis phenotype. TGF-β induced oxidative stress coincided with accumulation of DNA damage and elevated expression of senescence markers. Inactivation of Cdkn2a in the Gorab^Prx1 rescued the osteoporosis phenotype. Reduced colony formation and altered subpopulations of bone marrow stromal cells were normalized upon inactivation of Cdkn2a, thus further demonstrating the relevance of cellular senescence in the pathogenesis. Our results shed light on the causative role of a TGF-β-Nox4-senescence axis and therapeutic strategies for GO.

Keywords: Gorab; TGF‐beta; cellular senescence; gerodermia osteodysplastica; osteoporosis; proteoglycan; reactive oxygen species.

Abstract

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