Wnt/β-catenin signaling components and mechanisms in bone formation,homeostasis,and disease

Wnts are secreted,lipid-modified proteins that bind to different receptors on the cell surface to activate canonical or non-canonical Wnt signaling pathways,which control various biological processes throughout embryonic development and adult life.Aberrant Wnt signaling pathway underlies a wide range of human disease pathogeneses.

The role of 5′-adenosine monophosphate-activated protein kinase(AMPK)in skeletal muscle atrophy

As a key coordinator of metabolism,AMP-activated protein kinase(AMPK)is vitally involved in skeletal muscle maintenance.AMPK exerts its cellular effects through its function as a serine/threonine protein kinase by regulating many downstream targets and plays important roles in the development and growth of skeletal muscle.AMPK is activated by phosphorylation and exerts its function as a kinase in many processes,including synthesis and degradation of proteins,mitochondrial biogenesis,glucose uptake,and fatty acid and cholesterol metabolism.Skeletal muscle atrophy is a result of various diseases or disorders and is characterized by a decrease in muscle mass.The pathogenesis and therapeutic strategies of skeletal muscle atrophy are still under investigation.In this review,we discuss the role of AMPK in skeletal muscle metabolism and atrophy.We also discuss targeting AMPK for skeletal muscle treatment,including exercise,AMPK activators including 5-amino-4-imidazolecarboxamide ribonucleoside and metformin,and low-level lasers.These studies show the important roles of AMPK in regulating muscle metabolism and function;thus,the treatment of skeletal muscle atrophy needs to take into account the roles of AMPK.

Mechanical Sensitive Molecule MACF1 Promotes Osteoblast Differentiation

The decreased osteoblast differentiation associated with reduced bone formation is one main cause of microgravityinduced bone loss.Our previous studies have demonstrated that microtubule actin crosslinking factor 1(MACF1)is downregulated in association with the decreased osteoblast differentiation and bone formation under simulated microgravity conditions.These findings suggest that MACF1 is sensitive to mechanical condition and may be critical for osteoblast differentiation and bone formation.To verify this hypothesis,current study investigates the role and mechanism of MACF1 in regulatingosteoblast differentiation by adopting MACF1 knockdown(MACF1-KD)osteoblasts.The results showed that MACF1 knockdown suppressed mineralized nodules formation,alkaline phosphatase(ALP)activity,osteogenic gene expression andβ-catenin signaling transduction.Moreover,we used RNA sequencing(RNA-seq)and chromatin immunoprecipitation sequencing(ChIP-seq)to investigate further mechanism.Interestingly,we found that MACF1 sequesterd repressors of osteoblast differentiation in cytoplasm.In conclusion,MACF1 is sensitive to mechanical condition and plays key role in activatingβ-catenin signaling transduction and sequestering repressors of osteoblast differentiation,which further promotes osteoblast differentiation.

MACF1 deficiency suppresses tooth mineralization through IGF1 mediated crosstalk between odontoblasts and ameloblasts

Tooth mineralization is a ubiquitous and tightly regulated process involving complicated interactions between dental epithelium and mesenchyme.Key molecules in tooth mineralization remain poorly identified.Microtubule actin cross-linking factor 1(MACF1)is a spectraplakin protein that plays pivotal roles in the brain,muscle,lung,and bone developmental process.^(1-3) To study the specific functions of MACF1 in bone formation,we established Macf1 conditional knockout mice using the Cre-LoxP system driven by Osxterix promoter(Osx-Cre;Macf1^(f/f)).^(2) Not surprisingly,Osx-Cre;Macf1^(f/f) mice displayed the phenotypes of delayed ossification and decreased bone mass.Moreover,the OsxCre;Macf1^(f/f) mice unexpectedly showed a white and opaque appearance of incisors,contrary to the normal yellowbrown and transparent incisors.Since Osxterix is expressed in dental mesenchyme during tooth development,the abnormal tooth appearance might imply a new function of MACF1 in odontoblasts,or even ameloblasts.Therefore,the present study aimed to investigate the role of MACF1 during tooth development.

CD147 facilitates cisplatin resistance in ovarian cancer through FOXM1 degradation inhibition

Currently,the major therapy for patients with ovarian cancer includes post-cytoreductive surgery followed by chemotherapy of carboplatin or cisplatin plus paclitaxel.The rise of drug resistance is a substantial factor in cancer recurrence and mortality among ovarian cancer patients receiving cisplatin treatment.CD147 is widely expressed in a variety of cancer tissues1 and recognized as a drug target for its antibody drug Licartin which has been approved by China’s National Medicines and Pharmaceutical Administration.2 Even though many studies reported that CD147 is involved in the cisplatin resistance of varieties of cancers,3 its mechanism remains unclear.In this investigation,we uncovered a distinctive mechanism by which CD147 regulates cisplatin resistance through the proteasomal degradation of the transcription factor FOXM1,which is associated with DNA damage repair,in ovarian cancer cells.Our results suggest that targeting CD147 may have therapeutic implications for increasing cisplatin efficiency in the management of ovarian cancer.

An integrated genome-wide analysis identifies HUR/ELAVL1 as a positive regulator of osteogenesis through enhancing theβ-catenin signaling activity

Osteoporosis is a prevalent multifactorial bone disease with a strong genetic contribution.The heritability of traits that contribute to osteoporosis(bone mass,bone mineral density(BMD),bone size,bone loss and fractures)ranges from 50 to 85%,suggesting that a comprehensive understanding of the genetic basis may help identify new therapeutic targets.1 However,the genetic characteristics remain obscure,and the existing drug targets are associated with various challenges.Numerous studies have demonstrated that high-throughput sequencing data analysis is fruitful for identifying novel targets of human diseases.2 We therefore integrated GWAS and transcriptome analyses through Multi-marker Analysis of GenoMic Annotation(MAGMA)and weighted gene co-expression network analysis3(WGCNA)to identify new network modules and potential therapeutic genes for osteoporosis.As an illustration,the flow chart presenting the process of the present study was shown in Figure S1.

Microtubule actin crosslinking factor 1 functions as a novel therapeutic target in lung metastasis of osteosarcoma

Lung metastasis is the primary cause of death in osteosarcoma(OS)patients.1 A better understanding of the molecular mechanisms underlying OS tumorigenesis and metastasis is urgently needed to identify therapeutic targets.Microtubule actin crosslinking factor 1(MACF1),which belongs to the spectraplakin family of cytoskeletal crosslinking proteins,2 is critical for cell migration and polarization due to its regulation of the cytoskeleton.Recently,MACF1 was indicated to be involved in the metastatic invasion of some human cancers,3 but the function of MACF1 in OS is still unclear.