PMID- 27650914
OWN - NLM
STAT- MEDLINE
DCOM- 20171218
LR  - 20181113
IS  - 1873-2763 (Electronic)
IS  - 8756-3282 (Print)
IS  - 1873-2763 (Linking)
VI  - 93
DP  - 2016 Dec
TI  - A mathematical model of osteoclast acidification during bone resorption.
PG  - 167-180
LID - S8756-3282(16)30253-8 [pii]
LID - 10.1016/j.bone.2016.09.007 [doi]
AB  - Bone resorption by osteoclasts occurs through the creation of a sealed 
      extracellular compartment (ECC), or pit, adjacent to the bone that is 
      subsequently acidified through a complex biological process. The low pH of the 
      pit dissolves the bone mineral and activates acid proteases that further break 
      down the bone matrix. There are many ion channels, transporters, and soluble 
      proteins involved in osteoclast mediated resorption, and in the past few years, 
      there has been an increased understanding of the identity and properties of some 
      key proteins such as the ClC-7 Cl(-)/H(+) antiporter and the H(V)1 proton 
      channel. Here we present a detailed mathematical model of osteoclast 
      acidification that includes the influence of many of the key regulatory proteins. 
      The primary enzyme responsible for acidification is the vacuolar H(+)-ATPase 
      (V-ATPase), which pumps protons from the cytoplasm into the pit. Unlike the 
      acidification of small lysosomes, the pit is so large that protons become 
      depleted from the cytoplasm. Hence, proton buffering and production in the 
      cytoplasm by carbonic anhydrase II (CAII) is potentially important for proper 
      acidification. We employ an ordinary differential equations (ODE)-based model 
      that accounts for the changes in ionic species in the cytoplasm and the 
      resorptive pit. Additionally, our model tracks ionic flow between the cytoplasm 
      and the extracellular solution surrounding the cell. Whenever possible, the 
      properties of individual channels and transporters are calibrated based on 
      electrophysiological measurements, and physical properties of the cell, such as 
      buffering capacity, surface areas, and volumes, are estimated based on available 
      data. Our model reproduces many of the experimental findings regarding the role 
      of key proteins in the acidification process, and it allows us to estimate, among 
      other things, number of active pumps, protons moved, and the influence of 
      particular mutations implicated in disease.
CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
FAU - Marcoline, Frank V
AU  - Marcoline FV
AD  - Cardiovascular Research Institute, University of California, San Francisco, CA 
      94158, USA; Department of Pharmaceutical Chemistry, University of California, San 
      Francisco, CA 94158, USA.
FAU - Ishida, Yoichi
AU  - Ishida Y
AD  - Department of Philosophy, Ohio University, Athens, OH 45701, USA.
FAU - Mindell, Joseph A
AU  - Mindell JA
AD  - Membrane Transport Biophysics Unit, National Institute of Neurological Disorders 
      and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
FAU - Nayak, Smita
AU  - Nayak S
AD  - Swedish Center for Research and Innovation, Swedish Health Services, Seattle, WA 
      98122, USA.
FAU - Grabe, Michael
AU  - Grabe M
AD  - Cardiovascular Research Institute, University of California, San Francisco, CA 
      94158, USA; Department of Pharmaceutical Chemistry, University of California, San 
      Francisco, CA 94158, USA. Electronic address: michael.grabe@ucsf.edu.
LA  - eng
GR  - R21 GM100224/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160917
PL  - United States
TA  - Bone
JT  - Bone
JID - 8504048
RN  - 0 (Acids)
RN  - 0 (Chloride Channels)
RN  - 0 (Chloride-Bicarbonate Antiporters)
RN  - 0 (Chlorides)
RN  - 0 (Membrane Transport Proteins)
SB  - IM
MH  - Acids/*metabolism
MH  - Bone Resorption/*metabolism/*pathology
MH  - Cell Compartmentation
MH  - Cell Membrane/metabolism
MH  - Chloride Channels
MH  - Chloride-Bicarbonate Antiporters/metabolism
MH  - Chlorides/pharmacology
MH  - Cytoplasm/metabolism
MH  - Extracellular Space/metabolism
MH  - Hydrogen-Ion Concentration
MH  - Membrane Transport Proteins/metabolism
MH  - *Models, Biological
MH  - Osteoclasts/drug effects/*metabolism/*pathology
PMC - PMC5077641
MID - NIHMS816836
OTO - NOTNLM
OT  - Acidification
OT  - ClC-7
OT  - H(V)1
OT  - Mathematical model
OT  - Osteoclast
OT  - V-ATPase
EDAT- 2016/10/25 06:00
MHDA- 2017/12/19 06:00
PMCR- 2017/12/01
CRDT- 2016/09/22 06:00
PHST- 2016/03/12 00:00 [received]
PHST- 2016/08/16 00:00 [revised]
PHST- 2016/09/09 00:00 [accepted]
PHST- 2016/10/25 06:00 [pubmed]
PHST- 2017/12/19 06:00 [medline]
PHST- 2016/09/22 06:00 [entrez]
PHST- 2017/12/01 00:00 [pmc-release]
AID - S8756-3282(16)30253-8 [pii]
AID - 10.1016/j.bone.2016.09.007 [doi]
PST - ppublish
SO  - Bone. 2016 Dec;93:167-180. doi: 10.1016/j.bone.2016.09.007. Epub 2016 Sep 17.