Abstract
Myostatin is a crucial cytokine that is widely present in skeletal muscle and that negatively regulates the growth and development of muscle cells. Recent research has shown that myostatin might play an essential role in bone metabolism. In RAW264.7 cells and bone marrow monocytes (BMMCs), myostatin activates the expression of the II type receptor ActR II B. Here, we report that myostatin significantly promoted RANKL/M-CSF-induced osteoclastogenesis and activated NF-κB and MAPK pathways in vitro via the Ccdc50 gene. Overexpression of myostatin promoted osteoclastogenesis and osteoclastogenesis-related markers including c-Src, MMP9, CTR, CK, and NFATc1. Specifically, myostatin increased the phosphorylation of Smad2, which led to the activation of NF-κB and MAPK pathways to activate osteoclastogenesis. Ccdc50 was identified as a gene whose expression was highly decreased in osteoclastogenesis upon myostatin treatment, and it could inhibit the function of myostatin in osteoclastogenesis by blocking NF-κB and MAPKs pathways. Our study indicates that myostatin is a promising candidate target for inhibiting RANKL-mediated osteoclastogenesis and might participate in therapy for osteoporosis, and that the Ccdc50 gene plays a significant role in the regulatory process.
Highlights
Normal bone tissue is in a constant dynamic equilibrium state of bone formation and bone resorption
bone marrow monocytes (BMMCs) were treated with RANKL and M-CSF, while RAW264.7 cells were treated with RANKL for induction (Bharti et al, 2004; Lee et al, 2006)
We demonstrated that myostatin promotes osteoclastogenesis under the regulation of Ccdc50 in vitro
Summary
Normal bone tissue is in a constant dynamic equilibrium state of bone formation and bone resorption. NFATc1 promotes the expression of genes related to the proliferation and differentiation of osteoclasts. The induction of NFATc1/NFAT2 and the classical and nonclassical NF-κB pathways are necessary for transcription and translation of osteoclastogenesis-critical genes under the induction of RANKL/RANK-mediated activation. In this way, monocyte-derived macrophages fuse and differentiate into osteoclasts with mature osteolytic function (Walsh and Choi, 2014). The mitogen-activated protein kinase (MAPK) pathway represents a series of serine-threonine kinases in eukaryotes, and functions by phosphorylating other cytoplasmic proteins and directly regulating transcription after translocating from the cytoplasm to the nucleus (Hagemann and Blank, 2001). P38 phosphorylates its transactivation domain with the co-stimulation of c-fos both in vivo and in vitro (Tanos et al, 2005)
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