Regulation of Osteoblast Differentiation by Slit2 in Osteoblastic Cells

Sun, Hongli; Dai, Kerong; Tang, Tingting; Zhang, Xiaoling

doi:10.1159/000178020

Cited by 36 publications

(37 citation statements)

References 67 publications

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“…(39,40) Slit proteins, acting through their receptors Robo1/2, have been reported to inhibit osteoblast differentiation and function. (41) Finally, anti-NGF antibodies are undergoing testing in the clinic for the treatment of osteoarthritis and back pain, and one of the toxicities that has been well described is osteonecrosis of bone, although the mechanism for this toxicity has not been defined to date (42) and the effects of NGF (or NGF blockade) on bone metabolism have not been reported. Thus, although axonal guidance proteins and neurotrophins have been described to participate in bone remodeling, we hereby describe the unique role of Netrin-1 that acts both in an autocrine and a paracrine manner to synchronize osteoclast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Netrin-1 Is a Critical Autocrine/Paracrine Factor for Osteoclast Differentiation

Mediero

Ramkhelawon

Pérez-Aso

et al. 2014

Journal of Bone and Mineral Research

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Bone metabolism is a vital process that involves resorption by osteoclasts and formation by osteoblasts, which is closely regulated by immune cells. The neuronal guidance protein Netrin-1 regulates immune cell migration and inflammatory reactions, but its role in bone metabolism is unknown. During osteoclast differentiation, osteoclast precursors increase expression of Netrin-1 and its receptor Unc5b. Netrin-1 binds, in an autocrine and paracrine manner, to Unc5b to promote osteoclast differentiation in vitro, and absence of Netrin-1 or antibody-mediated blockade of Netrin-1 or Unc5b prevents osteoclast differentiation of both murine and human precursors. We confirmed the functional relationship of Netrin-1 in osteoclast differentiation in vivo using Netrin-1-deficient (Ntn1−/−) or wild-type (WT) bone marrow transplanted mice. Notably, Ntn1−/− chimeras have markedly diminished osteoclasts, as well as increased cortical and trabecular bone density and volume compared with WT mice. Mechanistic studies revealed that Netrin-1 regulates osteoclast differentiation by altering cytoskeletal assembly. Netrin-1 increases regulator of Rho-GEF subfamily (LARG) and repulsive guidance molecule (RGMa) association with Unc5b, which increases expression and activation of cytoskeletal regulators RhoA and focal adhesion kinase (FAK). Netrin-1 and its receptor Unc5b likely play a role in fusion of osteoclast precursors because Netrin-1 and DC-STAMP are tightly linked. These results identify Netrin-1 as a key regulator of osteoclast differentiation that may be a new target for bone therapies.

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Section: Discussionmentioning

confidence: 99%

Netrin-1 Is a Critical Autocrine/Paracrine Factor for Osteoclast Differentiation

Mediero

Ramkhelawon

Pérez-Aso

et al. 2014

Journal of Bone and Mineral Research

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“…As the most commonly used oral antidiabetic drug, metformin was reported to be protective against bone loss [5]. As we know, osteoblast proliferation is the key element affecting bone health [12], so it is necessary to research on the influences from high glucose and metformin. In this study, CCK8 assay at day 3 and day 7 revealed that high glucose could suppress the proliferation of osteoblasts, while metformin could attenuate this effect.…”

Section: Discussionmentioning

confidence: 99%

Metformin Rescues the MG63 Osteoblasts against the Effect of High Glucose on Proliferation

Shao

Cao

Song

et al. 2014

Journal of Diabetes Research

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Aims. To study the proliferation of osteoblasts and genes expression under normal glucose, high glucose, and metformin (Met). Methods. MG63 osteoblast-like cells were cultured in osteogenic medium supplemented with normal glucose (glucose 5.5 mmol/L) or high glucose (glucose 16.7 mmol/L) and metformin + high glucose (Met 300 μmol/L + glucose 16.7 mmol/L). Proliferation was detected with CCK-8 assay at days 1, 3, and 7. Real-time PCR and Western blot were performed to compare the expression of collagen I (Col I), osteocalcin (OCN), osteoprotegerin (OPG), receptor activator for NF-κB ligand (RANKL), and metal matrix proteinases 1 and 2 (MMP1, MMP2). Alkaline phosphatase (ALP) activity was also detected at days 6, 12, and 18. Results. Exposure to high glucose inhibited the proliferation of osteoblasts (P < 0.05), with suppressed OCN and OPG. Meanwhile, Col I, RANKL, MMP1, and MMP2 were unaffected. Metformin attenuated the suppression on proliferation with increased expression of Col I, OCN, and OPG, meanwhile suppressing MMP1 and MMP2. High glucose lowered the intracellular ALP, while metformin raised it. Metformin attenuated the downregulation of ALP completely at day 6, partly at day 12, but not at day 18. Conclusions. Metformin attenuated the suppression effect of high glucose to the osteoblast proliferation and gene expression, more prominently in earlier stage.

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“…Bone marrow mesenchymal stem cells (BMSCs) were harvested and cultured as described previously with modifications. Briefly, femora and tibiae were dissected free of surrounding soft tissues.…”

Section: Methodsmentioning

confidence: 99%

Osteoblast-Targeted suppression of PPARγ increases osteogenesis through activation of mTOR signaling

et al. 2013

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Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is an essential transcription factor for adipocyte differentiation. In mesenchymal stem cells, PPARγ has been assumed to play a negative role in osteoblastic differentiation, by working in an adipogenesis dependent manner, due to the reciprocal relationship between osteoblast and adipocyte differentiation. However, the direct role of PPARγ in osteoblast function is not fully understood, due in part to inadequate model systems. Here, we describe an adenoviral-mediated PPARγ knock-out system in which suppression of PPARγ in mesenchymal stem cells enhanced osteoblast differentiation and inhibited adipogenesis in vitro. Consistent with this in vitro observation, lipoatrophic A-ZIP/F1 mice, which do not form adipocytes, displayed a phenotype in which both cortical and trabecular bone was significantly increased compared to wild type mice. We next developed an inducible osteoblast-targeted PPARγ knock-out (Osx Cre/flox- PPARγ) mouse to determine the direct role of PPARγ in bone formation. Data from both in vitro cultures of mesenchymal stem cells and in vivo μCT analysis of bones suggests that suppression of PPARγ activity in osteoblasts significantly increased osteoblast differentiation and trabecular number. Endogenous PPARγ in mesenchymal stem cells and osteoblasts strongly inhibited Akt/mTOR/p70S6k activity and led to decreased osteoblastic differentiation. Therefore, we conclude that PPARγ modulates osteoblast differentiation and bone formation through both direct and indirect mechanisms. The direct mode, as shown here, involves PPARγ regulation of the mTOR pathway, while the indirect pathway is dependent on the regulation of adipogenesis.

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Regulation of Osteoblast Differentiation by Slit2 in Osteoblastic Cells

Cited by 36 publications

References 67 publications

Netrin-1 Is a Critical Autocrine/Paracrine Factor for Osteoclast Differentiation

Netrin-1 Is a Critical Autocrine/Paracrine Factor for Osteoclast Differentiation

Metformin Rescues the MG63 Osteoblasts against the Effect of High Glucose on Proliferation

Osteoblast-Targeted suppression of PPARγ increases osteogenesis through activation of mTOR signaling

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