BK Channel Deficiency in Osteoblasts Reduces Bone Formation via the Wnt/β-Catenin Pathway

Jiang, Lan; Yang, Qianhong; Gao, Jianjun; Yang, Jiahong; He, Jiaqi; Hong, Xin; Zhang, Xuemei

doi:10.14348/molcells.2021.0004

Cited by 8 publications

(8 citation statements)

References 49 publications

(51 reference statements)

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“…The Slo1 flox/flox mouse line, which has been described in our previously published study, 22 and Myf5‐Cre (Jackson Laboratories) mice were crossed to generate skeletal muscle specific Slo1‐deficient mice. The experiment was performed twice with independent cohorts.…”

Section: Methodsmentioning

confidence: 99%

Slo1 deficiency impaired skeletal muscle regeneration and slow‐twitch fibre formation

Xia

Wang

Jiang

et al. 2023

J cachexia sarcopenia muscle

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Background It has been observed that Slo1 knockout mice have reduced motor function, and people with certain Slo1 mutations have movement problems, but there is no answer whether the movement disorder is caused by the loss of Slo1 in the nervous system, or skeletal muscle, or both. Here, to ascertain in which tissues Slo1 functions to regulate motor function and offer deeper insight in treating related movement disorder, we generated skeletal muscle‐specific Slo1 knockout mice, studied the functional changes in Slo1‐deficient skeletal muscle and explored the underlying mechanism. Methods We used skeletal muscle‐specific Slo1 knockout mice (Myf5‐Cre; Slo1flox/flox mice, called CKO) as in vivo models to examine the role of Slo1 in muscle growth and muscle regeneration. The forelimb grip strength test was used to assess skeletal muscle function and treadmill exhaustion test was used to test whole‐body endurance. Mouse primary myoblasts derived from CKO (myoblast/CKO) mice were used to extend the findings to in vitro effects on myoblast differentiation and fusion. Quantitative real‐time PCR, western blot and immunofluorescence approaches were used to analyse Slo1 expression during myoblast differentiation and muscle regeneration. To investigate the involvement of genes in the regulation of muscle dysfunction induced by Slo1 deletion, RNA‐seq analysis was performed in primary myoblasts. Immunoprecipitation and mass spectrometry were used to identify the protein interacting with Slo1. A dual‐luciferase reporter assay was used to identify whether Slo1 deletion affects NFAT activity. Results We found that the body weight and size of CKO mice were not significantly different from those of Slo1flox/flox mice (called WT). Deficiency of Slo1 in muscles leads to reduced endurance (~30% reduction, P < 0.05) and strength (~30% reduction, P < 0.001). Although there was no difference in the general morphology of the muscles, electron microscopy revealed a considerable reduction in the content of mitochondria in the soleus muscle (~40% reduction, P < 0.01). We found that Slo1 was expressed mainly on the cell membrane and showed higher expression in slow‐twitch fibres. Slo1 protein expression is progressively reduced during muscle postnatal development and regeneration after injury, and the expression is strongly reduced during myoblast differentiation. Slo1 deletion impaired myoblast differentiation and slow‐twitch fibre formation. Mechanistically, RNA‐seq analysis showed that Slo1 influences the expression of genes related to myogenic differentiation and slow‐twitch fibre formation. Slo1 interacts with FAK to influence myogenic differentiation, and Slo1 deletion diminishes NFAT activity. Conclusions Our data reveal that Slo1 deficiency impaired skeletal muscle regeneration and slow‐twitch fibre formation.

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Section: Methodsmentioning

confidence: 99%

Slo1 deficiency impaired skeletal muscle regeneration and slow‐twitch fibre formation

Xia

Wang

Jiang

et al. 2023

J cachexia sarcopenia muscle

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“…The phosphorylation and degradation of β‐catenin is inhibited by the dissociation of GSK‐3b from Axin, which ultimately stabilizes β‐catenin, promoting its translocation into the nucleus where it induces the transcription of osteogenesis‐related genes 2,97 . USP8 stabilizes FZD expression through deubiquitination and ensures WNT‐induced osteogenesis 98 . USP4 inhibits osteoblast differentiation and bone formation by inhibiting Wnt/β‐catenin signalling via the removal of K63‐linked polyubiquitin chains from Dvl 99 .…”

Section: Effects Of Usps On Osteoblastogenesis and Bone Formationmentioning

confidence: 99%

“…USP7 directly interacts with the Axin through its TRAF domain and promotes Axin deubiquitination and stabilization, thereby inhibiting Wnt/β‐catenin signalling to regulate osteoblast differentiation 24 . Kcnma1, the gene encoding the BK channel, can upregulate the protein level of USP7 and then promote the degradation of β‐catenin in osteoblasts by stabilizing Axin, thereby inhibiting osteoblast differentiation and proliferation 98 . Mitogen‐activated protein kinase kinase 2 (MEKK2) has been found to mediate β‐catenin activation in osteoblasts via a mechanism that differs from that of the canonical WNT pathway 33 .…”

Section: Effects Of Usps On Osteoblastogenesis and Bone Formationmentioning

confidence: 99%

“…24 Kcnma1, the gene encoding the BK channel, can upregulate the protein level of USP7 and then promote the degradation of β-catenin in osteoblasts by stabilizing Axin, thereby inhibiting osteoblast differentiation and proliferation. 98 Mitogen-activated protein kinase kinase 2 (MEKK2) has been found…”

Section: Effects Of Usps On Osteoblastogenesis and Bone Formationmentioning

confidence: 99%

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Ubiquitin‐specific peptidases: Players in bone metabolism

et al. 2023

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Osteoporosis is an ageing‐related disease, that has become a major public health problem and its pathogenesis has not yet been fully elucidated. Substantial evidence suggests a strong link between overall age‐related disease progression and epigenetic modifications throughout the life cycle. As an important epigenetic modification, ubiquitination is extensively involved in various physiological processes, and its role in bone metabolism has attracted increasing attention. Ubiquitination can be reversed by deubiquitinases, which counteract protein ubiquitination degradation. As the largest and most structurally diverse cysteinase family of deubiquitinating enzymes, ubiquitin‐specific proteases (USPs), comprising the largest and most structurally diverse cysteine kinase family of deubiquitinating enzymes, have been found to be important players in maintaining the balance between bone formation and resorption. The aim of this review is to explore recent findings highlighting the regulatory functions of USPs in bone metabolism and provide insight into the molecular mechanisms governing their actions during bone loss. An in‐deep understanding of USPs‐mediated regulation of bone formation and bone resorption will provide a scientific rationale for the discovery and development of novel USP‐targeted therapeutic strategies for osteoporosis.

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“…BK channel modulators also affect the number of MG63 cells [ 158 ]. Evidence from KCNMA1 knockout mice suggests the Wnt/β-catenin signalling pathway to be among the main mechanisms of how BK channels influence bone homeostasis [ 159 ]. Er-xian Decoction (EXD) is a well-known prescription drug widely used to prevent and treat climacteric syndrome and osteoporosis in China.…”

Section: Calcium-dependent Potassium Channelsmentioning

confidence: 99%

Ca2+-Activated K+ Channels in Progenitor Cells of Musculoskeletal Tissues: A Narrative Review

Takács

Kovács

Ebeid

et al. 2023

IJMS

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Musculoskeletal disorders represent one of the main causes of disability worldwide, and their prevalence is predicted to increase in the coming decades. Stem cell therapy may be a promising option for the treatment of some of the musculoskeletal diseases. Although significant progress has been made in musculoskeletal stem cell research, osteoarthritis, the most-common musculoskeletal disorder, still lacks curative treatment. To fine-tune stem-cell-based therapy, it is necessary to focus on the underlying biological mechanisms. Ion channels and the bioelectric signals they generate control the proliferation, differentiation, and migration of musculoskeletal progenitor cells. Calcium- and voltage-activated potassium (KCa) channels are key players in cell physiology in cells of the musculoskeletal system. This review article focused on the big conductance (BK) KCa channels. The regulatory function of BK channels requires interactions with diverse sets of proteins that have different functions in tissue-resident stem cells. In this narrative review article, we discuss the main ion channels of musculoskeletal stem cells, with a focus on calcium-dependent potassium channels, especially on the large conductance BK channel. We review their expression and function in progenitor cell proliferation, differentiation, and migration and highlight gaps in current knowledge on their involvement in musculoskeletal diseases.

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BK Channel Deficiency in Osteoblasts Reduces Bone Formation via the Wnt/β-Catenin Pathway

Cited by 8 publications

References 49 publications

Slo1 deficiency impaired skeletal muscle regeneration and slow‐twitch fibre formation

Slo1 deficiency impaired skeletal muscle regeneration and slow‐twitch fibre formation

Ubiquitin‐specific peptidases: Players in bone metabolism

Ca2+-Activated K+ Channels in Progenitor Cells of Musculoskeletal Tissues: A Narrative Review

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