Disruption of bone remodelling by diseases such as osteoporosis results in an imbalance between bone formation by osteoblasts and resorption by osteoclasts. Research into these metabolic bone disorders is primarily performed in vivo; however, in the last decade there has been increased interest in generating in vitro models that can reduce or replace our reliance on animal testing. With recent advances in biomaterials and tissue engineering the feasibility of laboratory-based alternatives is growing; however, to date there are no established in vitro models of bone remodelling. In vivo, remodelling is performed by organised packets of osteoblasts and osteoclasts called bone multicellular units (BMUs). The key determinant of whether osteoclasts form and remodelling occurs is the ratio between RANKL, a cytokine which stimulates osteoclastogenesis, and OPG, its inhibitor. This review initially details the different circumstances, conditions, and factors which have been found to modulate the RANKL:OPG ratio, and fundamental factors to be considered if a robust in vitro model is to be developed. Following this, an examination of what has been achieved thus far in replicating remodelling in vitro using three-dimensional co-cultures is performed, before overviewing how such systems are already being utilised in the study of associated diseases, such as metastatic cancer and dental disorders. Finally, a discussion of the most important considerations to be incorporated going forward is presented. This details the need for the use of cells capable of endogenously producing the required cytokines, application of mechanical stimulation, and the presence of appropriate hormones in order to produce a robust model of bone remodelling.

/pdf/in-vitro-models-of-bone-remodelling-and-associated-disorders-3rzc5s094r.pdf

In vitro Models of Bone Remodelling and Associated Disorders

Lactoferrin promotes MC3T3-E1 osteoblast cells proliferation via MAPK signaling pathways.

Vaspin (visceral adipose tissue-derived serine protease inhibitor) is a newly discovered adipokine that widely participates in diabetes mellitus, polycystic ovarian syndrome and other disorders of metabolism. However, the effect of vaspin on the regulation of osteogenesis and the mechanism responsible are still unclear. Here, we found that vaspin can attenuate the osteogenic differentiation of the preosteoblast cell line MC3T3-E1 in a dose-dependent way; also, during this process, the expression of miRNA-34c (miR-34c) was significantly increased. Down-regulation of the expression of miR-34c in MC3T3-E1 diminished the osteogenic inhibitory effect of vaspin, while the up-regulation of miR-34c increased this effect through its target gene Runx2. Meanwhile, we found that vaspin could also activate the PI3K-Akt signalling pathway. Blocking the PI3K-Akt signalling pathway with specific inhibitors could decrease the osteogenic inhibitory effect of vaspin as well as the expression level of miR-34c. Furthermore, knock-down of miR-34c could promote the activation of Akt, which was probably realised by targeting c-met expression. Thus, PI3K-Akt and miR-34c constituted a modulation loop and controlled the expression of each other. Taken together, our study showed that vaspin could inhibit the osteogenic differentiation in vitro, and the PI3K-Akt/miR-34c loop might be the underlying mechanism.

/pdf/vaspin-regulates-the-osteogenic-differentiation-of-mc3t3-e1-3e8kur51xe.pdf

Vaspin regulates the osteogenic differentiation of MC3T3-E1 through the PI3K-Akt/miR-34c loop.

Targeting cancer with lactoferrin nanoparticles: recent advances.

SCOPE: Val‐Ser‐Glu‐Glu (VSEE), identified from duck egg white peptides, has been proven to facilitate calcium absorption in a previous study. Since prevention of osteoporosis is important, it might act as a potential cofactor in osteoporosis prevention. Therefore, the aim of this study is to investigate the regulation of VSEE on osteoporosis and abnormal lipid metabolisms. METHODS AND RESULTS: MC3T3‐E1 cell and ovariectomized (OVX) rat model are used to evaluate VSEE on regulation of bone and lipid metabolisms. Differentiation and matrix mineralization of preosteoblast are significantly increased by VSEE (p <0.05), which attributed to stimulating calcium influx, then to activating Wnt/β‐catenin signaling pathway and regulating runt‐related transcription factor 2 and osteoprotegerin. VSEE can cross Caco‐2/HT‐29 co‐cultured monolayer via paracellular pathway and peptide transporter 1 (PepT1), and can be detected in blood and maximum concentration is 122.84 ± 3.68 mg L⁻¹ at 60 min. Additionally, VSEE reverses bone loss and regulate dyslipidemia through Wnt/β‐catenin signaling pathway in OVX rats. Firmicutes phylum, Veillonellaceae, Prevotellaceae and six genera in VSEE group are significantly different compared with the Model group (p < 0.05). CONCLUSION: VSEE promotes bone growth and inhibit abnormal lipid metabolism in an OVX model through the regulation of intestinal microbiota compositions and Wnt/β‐catenin signal pathway.

Duck Egg White–Derived Peptide VSEE (Val‐Ser‐Glu‐Glu) Regulates Bone and Lipid Metabolisms by Wnt/β‐Catenin Signaling Pathway and Intestinal Microbiota

Lactoferrin (LF) has been established as a potent anabolic factor for bone health both in vivo and in vitro. However, the molecular mechanisms underlying LF's action are still largely unknown. Here, we explore the signaling pathways that mediate LF's beneficial effect on osteoblast differentiation. In primary osteoblast and preosteoblast MC3T3‐E1, LF promoted alkaline phosphatase (ALP)activity, osteocalcin (OCN) secretion, and mineralization. Along with this enhanced osteogenic differentiation, activation of p38 mitogen‐activated protein kinase (MAPK) was detected in LF‐treated MC3T3‐E1 cells. Downregulating p38 with selective inhibitor SB203580 or p38a small interfering RNA (siRNA) attenuated the effect of LF on osteogenesis. Furthermore, knockdown of p38α significantly decreased LF‐induced Runt‐related transcription factor 2 (Runx2) phosphorylation. According to previous studies and our results, we speculated that LF‐induced osteoblast proliferation and differentiation were two relatively separate processes controlled by extracellular signal‐regulated kinase 1/2 (ERK1/2) and p38 pathways, respectively. Besides p38 MAPK activation, protein kinase A(PKA) was also activated in MC3T3‐E1 cells. PKA inhibitor H89 significantly inhibited LF‐induced p38 activation, ALP activity, and OCN secretion, indicating that PKA possibly acted as an upstream kinase of p38. In order to further identify the role of LF's receptor low-density lipoprotein receptor‐related protein 1 (LRP1), we constructed LRP1 stable‐knockdown MC3T3‐E1 cells. Neither LRP1 antagonist receptor associated protein (RAP), nor LRP1 knockdown approach could attenuate the LF‐induced osteogenesis, implying that LF stimulated osteoblast differentiation via an LRP1‐independent pathway. Taken together, the present work indicated that LF stimulated MC3T3‐E1 preosteoblast differentiation mainly through LRP1‐independent PKA and p38 signaling pathways. These results provided the first evidence of the signaling mechanisms of LF's effect on osteoblast differentiation.

Lactoferrin Stimulates Osteoblast Differentiation Through PKA and p38 Pathways Independent of Lactoferrin's Receptor LRP1

Lactoferrin-induced growth factors and cytokines expression profile in pre-osteoblast MC3T3-E1 cell and LRP1 stable knockdown MC3T3-E1 cell

Interaction of lactoferrin and its peptides LfcinB4-14 and LfampinB with dipalmitoylglycero-phosphocholine (DPPC) and dipalmitoylglycero-phosphoglycerol (DPPG) liposomes were studied by means of Raman spectroscopy. In our study, conformational changes in the phospholipid molecules were investigated by measuring the intensities of 2 847 and 2 882 cm(-1) Raman bands which are assigned to acyl chains' symmetric and asymmetric C-H stretching vibrations. The addition of lactoferrin and its peptides LfcinB4-14 and LfampinB caused a decrease in the 2 882 cm(-1) intensity of DPPG liposomes, thus the order parameter for the lateral interactions between chains S(lat) decreased from 0.19 to 0.17, 0.14 and 0.12 respectively. On the contrary, the intensities at 2 847 and 2 882 cm(-1) of DPPC liposomes were poorly affected by lactoferrin and its peptides. The results show that lactoferrin and its peptides present a stronger effect on the molecular structure and order degree of anionic lipid DPPG than that of zwitterionic lipid DPPC. This suggests that lactoferrin, LfcinB4-14 and LfampinB can interact and combine with the negatively charged DPPG liposomes by electrostatic interaction and perform its antibacterial activity. Besides, LfcinB4-14 and LfampinB can affect the lipid more strongly than lactoferrin.

Interaction of lactoferrin and its peptides with DPPC and DPPG liposomes studied by Raman spectroscopy

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Lactoferrin Stimulates Osteoblast Differentiation Through PKA and p38 Pathways Independent of Lactoferrin's Receptor LRP1

Lactoferrin-induced growth factors and cytokines expression profile in pre-osteoblast MC3T3-E1 cell and LRP1 stable knockdown MC3T3-E1 cell

Interaction of lactoferrin and its peptides with DPPC and DPPG liposomes studied by Raman spectroscopy