BMP Signaling Mediated by BMPR1A in Osteoclasts Negatively Regulates Osteoblast Mineralization Through Suppression of Cx43

Osteoblasts and osteoclasts are well orchestrated through different mechanisms of communication during bone remodeling. Previously, we found that osteoclast‐specific disruption of one of the BMP receptors, Bmpr1a, results in increased osteoblastic bone formation in mice. We hypothesized that BMPR1A signaling in osteoclasts regulates production of either membrane bound proteins or secreted molecules that regulated osteoblast differentiation. In our current study, we co‐cultured wild‐type osteoblasts with either control osteoclasts or osteoclasts lacking BMPR1A signaling activity. We found that loss of Bmpr1a in osteoclasts promoted osteoblast mineralization in vitro. Further, we found that the expression of Cx43/Gja1 in the mutant osteoclasts was increased, which encoded for one of the gap junction proteins connexin 43/gap junction alpha 1. Knockdown of Gja1 in the mutant osteoclasts for Bmpr1a reduced osteoblastic mineralization when co‐cultured. Our findings suggest that GJA1 may be one of the downstream targets of BMPR1A signaling in osteoclasts that mediates osteoclast–osteoblast communication during bone remodeling. J. Cell. Biochem. 118: 605–614, 2017. © 2016 Wiley Periodicals, Inc.Disruption of Bmpr1a in osteoclasts promoted osteoblast mineralization when co‐cultured. Up‐regulation of gap junction Cx43/Gja1 in mutant osteoclasts is responsible for the enhanced osteoblast function.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135668/1/jcb25746_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135668/2/jcb25746.pd

Polymeric pH nanosensor with extended measurement range bearing octaarginine as cell penetrating peptide

A synthetic peptide octaarginine which mimics human immunodeficiency virus‐1, Tat protein is used as cell penetrating moiety for new pH nanosensors which demonstrate enhanced cellular uptake and expanded measurement range from pH 3.9 to pH 7.3 by simultaneously incorporating two complemental pH‐sensitive fluorophores in a same nanoparticle. The authors believe that this triple fluorescent pH sensor provides a new tool to pH measurements that can have application in cellular uptake mechanism study and new nanomedicine design

Optimal Computing Budget Allocation for Ordinal Optimization in Solving Stochastic Job Shop Scheduling Problems

We focus on solving Stochastic Job Shop Scheduling Problem (SJSSP) with random processing time to minimize the expected sum of earliness and tardiness costs of all jobs. To further enhance the efficiency of the simulation optimization technique of embedding Evolutionary Strategy in Ordinal Optimization (ESOO) which is based on Monte Carlo simulation, we embed Optimal Computing Budget Allocation (OCBA) technique into the exploration stage of ESOO to optimize the performance evaluation process by controlling the allocation of simulation times. However, while pursuing a good set of schedules, “super individuals,” which can absorb most of the given computation while others hardly get any simulation budget, may emerge according to the allocating equation of OCBA. Consequently, the schedules cannot be evaluated exactly, and thus the probability of correct selection (PCS) tends to be low. Therefore, we modify OCBA to balance the computation allocation: (1) set a threshold of simulation times to detect “super individuals” and (2) follow an exclusion mechanism to marginalize them. Finally, the proposed approach is applied to an SJSSP comprising 8 jobs on 8 machines with random processing time in truncated normal, uniform, and exponential distributions, respectively. The results demonstrate that our method outperforms the ESOO method by achieving better solutions

Discovery of Novel 4-Arylisochromenes as Anticancer Agents Inhibiting Tubulin Polymerization

XJP-L (8), a derivative of the natural product (±)-7,8-dihydroxy-3-methylisochroman-4-one isolated from the peel of Musa sapien tum L., was found to exhibit weak inhibitory activity of tubulin polymerization (IC50 = 10.6 μM) in our previous studies. Thus, a series of 4-arylisochromene derivatives were prepared by incorporating the trimethoxyphenyl moiety into 8, among which compound (±)-19b was identified as the most potent compound with IC50 values ranging from 10 to 25 nM against a panel of cancer cell lines. Further mechanism studies demonstrated that (±)-19b disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis, and depolarized mitochondria of K562 cells. Moreover, (±)-19b exhibited potent in vitro antivascular and in vivo antitumor activities. Notably, the R-configured enantiomer of (±)-19b, which was prepared by chiral separation, was slightly more potent than (±)-19b and was much more potent than the S-configured enantiomer in both antiproliferative and antitubulin assays. Our findings suggest that (±)-19b deserves further research as a potential antitubulin agent for the treatment of cancers

Deletion of BMP receptor type IB decreased bone mass in association with compromised osteoblastic differentiation of bone marrow mesenchymal progenitors

We previously found that disruption of two type I BMP receptors, Bmpr1a and Acvr1, respectively, in an osteoblast-specific manner, increased bone mass in mice. BMPR1B, another BMP type I receptor, is also capable of binding to BMP ligands and transduce BMP signaling. However, little is known about the function of BMPR1B in bone. In this study, we investigated the bone phenotype in Bmpr1b null mice and the impacts of loss of Bmpr1b on osteoblasts and osteoclasts. We found that deletion of Bmpr1b resulted in osteopenia in 8-week-old male mice, and the phenotype was transient and gender specific. The decreased bone mass was neither due to the changes in osteoblastic bone formation activity nor osteoclastic bone resorption activity in vivo. In vitro differentiation of Bmpr1b null osteoclasts was increased but resorption activity was decreased. Calvarial pre-osteoblasts from Bmpr1b mutant showed comparable differentiation capability in vitro, while they showed increased BMP-SMAD signaling in culture. Different from calvarial pre-osteoblasts, Bmpr1b mutant bone marrow mesenchymal progenitors showed compromised differentiation in vitro, which may be a reason for the osteopenic phenotype in the mutant mice. In conclusion, our results suggested that BMPR1B plays distinct roles from BMPR1A and ACVR1 in maintaining bone mass and transducing BMP signaling

Design, synthesis and biological evaluation of quinoline-indole derivatives as anti-tubulin agents targeting the colchicine binding site

A series of novel isocombretastatin A-4 (isoCA-4) analogs were designed and synthesized by replacing 3,4,5-trimethoylphenyl and isovanillin of isoCA-4 with quinoline and indole moieties, respectively. The structure activity relationships (SARs) of these synthesized quinoline-indole derivatives have been intensively investigated. Two compounds 27c and 34b exhibited the most potent activities against five cancer cell lines with IC50 values ranging from 2 to 11 nM, which were comparable to those of Combretastatin A-4 (CA-4, 1). Further mechanism investigations revealed that 34b effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further cellular mechanism studies elucidated that 34b disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, induced apoptosis and depolarized mitochondria of K562 cells. Moreover, 34b displayed potent anti-vascular activity in both wound healing and tube formation assays. Importantly, 27c and 34b significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, suggesting that 27c and 34b deserve further research as potent antitumor agents for cancer therapy