Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

Complications with the use of bone morphogenetic protein 2 (BMP-2) in spine surgery

Bone morphogenetic proteins (BMPs) are responsible for bone formation during embryogenesis and bone regeneration and remodeling. The osteoinductive action of BMPs, especially BMP-2 and BMP-7, has led to their use in a range of insurmountable treatments where intervention is required for effective bone regeneration. Introduction of BMP products to the market, however, was not without reports of multiple complications and side effects. Aiming for optimization of the therapeutic efficacy and safety, efforts have been focused on improving the delivery of BMPs to lower the administered dose, localize the protein, and prolong its retention time at the site of action. A major challenge with these efforts is that the protein stability should be maintained. With this review we attempt to shed light on how the stability of BMPs can be affected in the formulation and delivery processes. We first provide a short overview of the current standing of the complications experienced with BMP products. We then discuss the different delivery parameters studied in association with BMPs, and their influence on the efficacy and safety of BMP treatments. In particular, the literature addressing the stability of BMPs and their possible interactions with components of the delivery system as well as their sensitivity to conditions of the formulation process is reviewed. In summary, recent developments in the fields of bioengineering and biopharmaceuticals suggest that a good understanding of the relationship between the formulation/delivery conditions and the stability of growth factors such as BMPs is a prerequisite for a safe and effective treatment.

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Formulation, Delivery and Stability of Bone Morphogenetic Proteins for Effective Bone Regeneration.

Cell stiffness determined by atomic force microscopy and its correlation with cell motility

Background Nucleotide metabolism is a critical pathway that generates purine and pyrimidine molecules for DNA replication, RNA synthesis, and cellular bioenergetics. Increased nucleotide metabolism supports uncontrolled growth of tumors and is a hallmark of cancer. Agents inhibiting synthesis and incorporation of nucleotides in DNA are widely used as chemotherapeutics to reduce tumor growth, cause DNA damage, and induce cell death. Thus, the research on nucleotide metabolism in cancer is primarily focused on its role in cell proliferation. However, in addition to proliferation, the role of purine molecules is established as ligands for purinergic signals. However, so far, the role of the pyrimidines has not been discussed beyond cell growth. Scope of the review In this review we present the key evidence from recent pivotal studies supporting the notion of a non-proliferative role for pyrimidine metabolism (PyM) in cancer, with a special focus on its effect on differentiation in cancers from different origins. Major conclusion In leukemic cells, the pyrimidine catabolism induces terminal differentiation toward monocytic lineage to check the aberrant cell proliferation, whereas in some solid tumors (e.g., triple negative breast cancer and hepatocellular carcinoma), catalytic degradation of pyrimidines maintains the mesenchymal-like state driven by epithelial-to-mesenchymal transition (EMT). This review further broadens this concept to understand the effect of PyM on metastasis and, ultimately, delivers a rationale to investigate the involvement of the pyrimidine molecules as oncometabolites. Overall, understanding the non-proliferative role of PyM in cancer will lead to improvement of the existing antimetabolites and to development of new therapeutic options.

https://findresearcher.sdu.dk:8443/ws/files/168751771/1_s2.0_S221287782030034X_main.pdf

A non-proliferative role of pyrimidine metabolism in cancer.

Bone morphogenetic protein 2 (BMP2) has been shown to modulate the proliferation and differentiation of breast cancer cells. However, the biochemical effects and mechanisms remain unknown. In this paper, the effects of recombinant human BMP2 on the migration of MCF-7 cells—one breast cancer cell line, using transwell and wound healing experiments, as well as on the cellular morphology, cytoskeleton, cell surface adhesion, and stiffness detected at subcellular level by an atomic force microscope, were investigated. After BMP2 treatment, the untreated round-shaped MCF-7 cells transformed to a spindle-like shape with lots of specialized structures, such as lamellipodia, filopodia, membrane protrusions, and others, which are essential for cellular migration or spreading. Moreover, flow cytometry quantitatively detected the BMP2-induced changes in the expression of adhesion molecules, a significant rise of CD44, and a remarkable drop of E-cadherin. The data indicated that BMP2 promoted the migration and invasion of MCF-7 cells by regulating the reorganization of cytoskeleton and the expression of adhesion molecules in/on the cells. Thus, it is very imperative to evaluate the oncogenicity of BMP2 when used in tissue engineering.

BMP2 promotes migration and invasion of breast cancer cells via cytoskeletal reorganization and adhesion decrease: an AFM investigation

Summary: The integrity and adhesion properties ofendothelium playvital roles during atherosclerosis. Itis well known that oxidized low-density lipoprotein(Ox-LDL)inﬂuencesmanyphysiologicalactivitiesormechanical properties of endothelial cells. However,the effects of Ox-LDL on the integrity and nonspe-ciﬁc adhesion properties of endothelial cells are stillunclear. In this study, using the topographical imag-ing and force measurement functions of atomic forcemicroscopy(AFM),wefoundthatOx-LDLcantran-sientlyweakentheintegrityofendotheliumbyimpair-ingcellspreadingofendothelialcellsanddecreasetheattachment of irrelevant blood cells to endotheliumby impairing the nonspeciﬁc adhesion property ofendothelial cells. The AFM-based data provide im-portant information for understanding the effects ofOx-LDLonendothelialcellsorduringatherogenesis.SCANNING 00: 1–8, 2012. C 2012 Wiley Periodi-cals, Inc. Key words: atherosclerosis, oxidized low-densitylipoprotein (Ox-LDL), human umbilical veinendothelial cells (HUVECs), atomic forcemicroscopy (AFM), cell spreading, adhesive force

AFM Investigation on Ox‐LDL‐Induced Changes in Cell Spreading and Cell‐Surface Adhesion Property of Endothelial Cells

We developed novel methods to directly quantify cell spreading rate. By comparing our methods with traditional methods, we found that the enhancement effects of fetal calf serum (FCS) or the inhibitory effects of exogenous ganglioside GM1 occurred at different stages of cell spreading. GM1 mainly influenced the early and late stages of cell spreading of HUVECs. In the presence of 0.5% FCS, GM1 significantly impaired the area-based spreading rates (127.4 ± 35.7 μm(2)/h and 22.2 ± 3.8 μm(2)/h, respectively) on the early (0-0.5 h) and late (12-24 h) stages of cell spreading compared with the controls (238.1 ± 11.7 μm(2)/h and 35.4 ± 19.5 μm(2)/h, respectively), which was confirmed by the data on the GM1-induced changes in average length of actin filaments during cell spreading. The real-time observation and quantification of cold-induced de-spreading of GM1-free or GM1-treated HUVECs further confirmed that GM1 can influence cell de-spreading process having inhibitory (0-10 min) or enhancement (10-20 min or 40-50 min) effects on different stages. The methods can be recruited for investigating effects of other reagents on different stages of cell spreading.

Effects of exogenous ganglioside GM1 on different stages of cell spreading studied by directly quantifying spreading rate.

Previously, we found that exogenous ganglioside GM3 had an antiatherosclerotic efficacy and that its antiatherosclerotic efficacy could be enhanced by reconstituted high-density lipoprotein (rHDL). In this study, we hypothesized that GM3-functionalized rHDL (i.e., GM3-rHDL) as a nanocarrier can promote the efficacy of traditional antiatherosclerotic drugs (e.g., statins). To test this hypothesis, lovastatin (LT) was used as a representative of statins, and LT-loaded GM3-rHDL nanoparticle (LT-GM3-rHDL or LT@GM3-rHDL; a mean size of ~142 nm) and multiple controls (e.g., GM3-rHDL without LT, LT-loaded rHDL or LT-rHDL, and other nanoparticles) were prepared. By using two different microsphere-based methods, the presences of apolipoprotein A-I (apoA-I) and/or GM3 in nanoparticles and the apoA-I-mediated macrophage-targeting ability of apoA-I/rHDL-containing nanoparticles were verified in vitro. Moreover, LT-GM3-rHDL nanoparticle had a slowly sustained LT release in vitro and the strongest inhibitory effect on the foam cell formation of macrophages (a key event of atherogenesis). After single administration of rHDL-based nanoparticles, a higher LT concentration was detected shortly in the atherosclerotic plaques of apoE−/− mice than non-rHDL-based nanoparticles, suggesting the in vivo plaque-targeting ability of apoA-I/rHDL-containing nanoparticles. Finally, among all nanoparticles LT-GM3-rHDL induced the largest decreases in the contents of blood lipids and in the areas of atherosclerotic plaques at various aortic locations in apoE−/− mice fed a high-fat diet for 12 weeks, supporting that LT-GM3-rHDL has the best in vivo antiatherosclerotic efficacy among the tested nanoparticles. Our data imply that GM3-functionalized rHDL (i.e., GM3-rHDL) can be utilized as a novel nanocarrier to enhance the efficacy of traditional antiatherosclerotic drugs (e.g., statins).

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Ganglioside GM3-Functionalized Reconstituted High-Density Lipoprotein (GM3-rHDL) as a Novel Nanocarrier Enhances Antiatherosclerotic Efficacy of Statins in apoE−/− C57BL/6 Mice

ABSTRACT Objective: Chinese herbal medicine formula and calcium antagonist are commonly used medicines for hypertension in China. This study aims to examine the efficacy and safety of for the treatment of Chinese herbal medicine formula combined calcium antagonist hypertension. Methods: PubMed, the Cochrane library, CNKI, VIP, Sinomed, and Wanfang Database were searched up to January 31, 2021. Data analysis was performed using the Recman 5.3. The source of clinical heterogeneity used stata16.0 for sensitivity analysis. Results: 17 RCTs and 1587 cases were finally included. The results shows that the traditional Chinese medicine decoction combined with calcium antagonists is better than calcium antagonists alone in the treatment of hypertension. In addition, it can effectively alleviate the adverse reactions caused by calcium antagonists. However, due to the low quality of methodology and the small-scale research, more high-quality clinical trials are still needed for verification.

Wenxiang Shao

Papers

BMP2 promotes migration and invasion of breast cancer cells via cytoskeletal reorganization and adhesion decrease: an AFM investigation

AFM Investigation on Ox‐LDL‐Induced Changes in Cell Spreading and Cell‐Surface Adhesion Property of Endothelial Cells

Effects of exogenous ganglioside GM1 on different stages of cell spreading studied by directly quantifying spreading rate.

Ganglioside GM3-Functionalized Reconstituted High-Density Lipoprotein (GM3-rHDL) as a Novel Nanocarrier Enhances Antiatherosclerotic Efficacy of Statins in apoE−/− C57BL/6 Mice

Chinese herbal medicine formula combined with calcium antagonist in the treatment of hypertension: a systematic review and meta-analysis