Functional Roles of Netrin-1 in Osteoblast Differentiation

Abstract

Bone tissue is constantly being remodeled to maintain its homeostasis by osteoblasts and the resorption by osteoclasts (1). The function of bone tissue is regulated by several factors which other organs produce to communicate with bones. Indeed, the vessels and nerves inside bone are essential for bone development and remodeling (2, 3). Previous studies have demonstrated that neural and vascular regulation factors, such as semaphorins and netrins, orchestrate bone metabolism. We have demonstrated that semaphorin 3A, which is a diffusible axonal chemorepellent that has an important role in axon guidance, regulates bone remodeling indirectly by modulating sensory nerve development and also found that it enhances the elongation of dendrite in osteocytes (4, 5). Semaphorin 3A exerts an osteoprotective effect by both suppressing bone resorption and increasing bone formation (6).Mammalian netrins including the secreted proteins (netrin-1, netrin-3, netrin-4 and netrin-5) and membrane-bound proteins (netrin-G1 and netrin-G2) are involved in the regulation of both axon guidance and angiogenesis (7). The netrin system comprises of seven receptors including neogenin (Neo1), deleted in colorectal carcinoma (DCC), Unc5A, Unc5B, Unc5C, Unc5D, adenosine 2b (A2b), and Down syndrome cell adhesion molecule (DSCAM) (7). Among these netrins, netrin-1 (Ntn1) has involved in cytoskeleton reorganization and in epithelial cell adhesion and migration in lung, mammary gland, and pancreas (8-10). Recent studies showed that Ntn1 plays a crucial role in osteoclast differentiation (11,12). As the function of osteoclasts is regulated by Ntn1, the question whether Ntn1 affects cellular function in osteoblasts has been raised. However, little is known about the role of Ntn1 in osteoblasts. In this study, we explore whether Ntn1 affects the function of osteoblasts. Materials and ΜethodsCell culture, reagents and transfection. The mouse pre-osteoblastic cell line MC3T3-E1 cells which were kindly provided from Dr. Toru Ogasawara (Department of Oral and Maxillofacial Surgery, The University of Tokyo, Japan) were maintained in the medium, 321

Physiological Signatures of Dual Embryonic Origins in Mouse Skull Vault

“…2) Fb tissue showed higher levels of some genes related to proliferation, selfrenewal or stem cell niche, such as Ptgfr, which acts as a strong mitogenic and survival agent on osteoblasts [12], but Pb tissue expressed high levels of genes associated with anti-proliferative properties, such as AATK and SGOL1, which are both apoptosisrelated proteins [13]. 3) Pb tissue exhibited higher level of osteoblast differentiation by up-regulating genes expressions of Msx2, Twist2, two key transcriptional factor for osteoblast differentiation [14], as well as Ntn1, which plays vital role in osteoblast and osteoclast differentiation [15]. However, Fb tissues expressed higher levels of Ostn and Nell1.…”

Does osteogenic potential of clonal human bone marrow mesenchymal stem/stromal cells correlate with their vascular supportive ability?

“…In contrast to CFU-F clones with high osteoblastic potential, a number of genes were upregulated in CFU-F clones with low osteogenic potential. These include (i) NOTCH2 (twofold upregulated; p = 5.57E−04, FDR = 0.047), which plays a predominant role in suppressing osteoblastogenesis [81]; (ii) COL12A1 (3.49-fold upregulated; p = 1.33E−06, FDR = 1.94E−03), a collagen-encoding gene that forms complexes mediating osteoblast interactions during osteogenesis [82]; (iii) UNC5B (4.51-fold upregulated; p = 4.00E−05, FDR = 1.57E−02), which encodes a netrin receptor involved in negative regulation of osteoblast differentiation by netrin 1 [83, 84]; (iv) TNFRSF19 (4.38-fold upregulated; p = 6.75E−04; FDR = 4.92E−02), which encodes a factor that regulates human MSC differentiation into osteoblasts or adipocytes [85]; and (v) EGLN1 , (2.49-fold upregulated; p = 4.02E−05; FDR = 0.016) which encodes PHD2 (propyl hydroxylase domain 2 protein), a cellular oxygen sensor involved in HIF-α proteosomal degradation in normoxic conditions and inhibiting osteogenic differentiation of MSCs and their upregulation of proangiogenic factors [86–88]. Additionally, in those CFU-F with poor vascular supportive capacity, there was an upregulation of TNFSF15 (VEGI), a potent inhibitor of endothelial proliferation and angiogenesis [89].…”

Netrin-4 Promotes Differentiation and Migration of Osteoblasts

“…Recently, we found that Ntn1 inhibits osteoblast differentiation and the combination of two netrin receptors is essential for regulating osteoblast differentiation by Ntn1 (30). Further investigations will be required to clarify the role of netrins in bone metabolism.…”