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USP8-mediated mitochondrial regulation in osteoclasts is essential for skeletal development

ABSTRACT: Aberrant protein regulatory pathways disrupt bone homeostasis and contribute to skeletal diseases. Many of cysteine protease family of deubiquitinating enzymes (DUBs) are critical for regulation of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we demonstrate that the DUB ubiquitin-specific protease 8 (USP8) is highly expressed in osteoclasts and its deletion impairs osteoclast development and bone resorption activity. Deletion of USP8 in osteoclasts (Usp8Ctsk) results in low bone mass due to defective endochondral ossification and short stature resulting from abnormal growth plate structure. Mechanistically, USP8 deficiency in osteoclasts dampens mitochondrial number, activity, oxidative phosphorylation, and mitophagy, while reactive oxygen species (ROS) inflammatory responses are increased in these cells. Moreover, USP8-deficient osteoclasts in metaphysis produce secretory factors that hinder both cartilage formation in the growth plate and trabecular bone formation. Collectively, these findings identify USP8 as a key regulator of osteoclast development and secretory factor production, shaping the microenvironment essential for skeletal development.

ORGANISM(S): Mus musculus

PROVIDER: GSE302739 | GEO | 2026/03/05

REPOSITORIES: GEO

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Project description:Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity. Total bone marrow cells were prepared from the femurs and tibias of 8-10-week-old C57BL/6 mice and cultured in the presence of M-CSF (100ng/ml) for 3 days as described previously (Takeshita et al., 2000 JBMR 15:1477-1488). Cells were harvested with 0.02% EDTA/PBS and used as bone marrow macrophages (BMMs). These BMMs were cultured in the presence of M-CSF (100 ng/ml) and RANKL (100ng/ml) for 2 days. TRAP positive mononuclear cells were harvested and used as pre-osteoclasts (pOC). These pOC cells were further cultured in the presence of M-CSF and RANKL for 2 days in normal plastic plate or on dentin slices. After 2 days, multinucleated TRAP positive mature osteoclasts were generated as mature osteoclasts on plate (mOCp) and mature resorbing osteoclasts on dentin (mOCd), respectively. RNAs were extracted from four different stages of osteoclast lineage cells; BMMs, pOC, mOCp and mOCd, and used for microarray analysis.

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USP8-mediated mitochondrial regulation in osteoclasts is essential for skeletal development

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