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ZMAT1 promotes osteoclast formation and bone loss through TRIM46 mediated YAP1 degradation. [CUT&Tag]

ABSTRACT: Osteoclasts and osteoblasts play a critical role in bone remodeling, and their dysregulation leads to pathological bone loss. However, precise regulation of their differentiation remains not fully elucidated. This study investigates the role of transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and reduced bone resorption. Mechanististically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which then regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency also enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE274533 | GEO | 2024/08/15

REPOSITORIES: GEO

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ZMAT1 promotes osteoclast formation and bone loss through TRIM46 mediated YAP1 degradation.

Project description:Osteoclasts and osteoblasts play a critical role in bone remodeling, and their dysregulation leads to pathological bone loss. However, precise regulation of their differentiation remains not fully elucidated. This study investigates the role of transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and reduced bone resorption. Mechanististically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which then regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency also enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis.

2024-08-15 | GSE274540 | GEO

ZMAT1 promotes osteoclast formation and bone loss through TRIM46 mediated YAP1 degradation II

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Project description:Wolff’s law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads. These models predict the existence of a mechanostat that links strain induced by mechanical forces to skeletal remodeling. However, how the mechanostat influences bone remodeling remains elusive. Here, we find that Piezo1 deficiency in osteoblastic cells leads to loss of bone mass and spontaneous fractures with increased bone resorption. Furthermore, Piezo1-deficient mice are resistant to further bone loss and bone resorption induced by hind limb unloading, demonstrating that PIEZO1 can affect osteoblast-osteoclast crosstalk in response to mechanical forces. At the mechanistic level, in response to mechanical loads, PIEZO1 in osteoblastic cells controls the YAP-dependent expression of type II and IX collagens. In turn, these collagen isoforms regulate osteoclast differentiation. Taken together, our data identify PIEZO1 as the major skeletal mechanosensor that tunes bone homeostasis.

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