A mathematical model of osteoclast acidification during bone resorption

Abstract

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 HV1 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.

Reactive Oxygen Species in Osteoclast Differentiation and Possible Pharmaceutical Targets of ROS-Mediated Osteoclast Diseases

“…Briefly, OCs originate through a process involving multiple steps, starting from the commitment of hematopoietic stem cells into the monocyte-macrophage lineage. Then, premature OCs proliferate into mature OCs, followed by OC polarization induced by integrin αvβ3 which forms a resorptive machinery that facilitates the attachment of OCs to the bone matrix and subsequent formation of a ruffled border that results in the process of resorption [5,6]. OC differentiation from hematopoietic progenitor lineage requires macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) to undergo osteoclastic differentiation [1,2,3,4,5,6].…”

“…Some key elements regulating this process are systemic hormones, nerve signals, vascular agents, and growth factors, such as cytokines, chemokines, cell adhesion molecules, molecules of the extracellular matrix, and proteinases. Interestingly, the pro-inflammatory cytokines, such as IL-1 and TNF-α have been implicated in the formation and functional activities of OCs [1,2,3,4,5,6]. The binding of RANKL to its receptor RANK, recruits the adapter molecule, TNF receptor associated factor 6 (TRAF6), resulting in the activation of a signal cascade of various mitogen activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK), which in turn activates nuclear factor of activated T cells 1 (NFATc1), a key step in RANKL-induced OC differentiation (Figure 1).…”

Phosphoserine Functionalized Cements Preserve Metastable Phases, and Reprecipitate Octacalcium Phosphate, Hydroxyapatite, Dicalcium Phosphate, and Amorphous Calcium Phosphate, during Degradation, In Vitro

“…Disc shaped samples were incubated for 14 days in liquids representing the dissolution environment at sites of active resorption in vitro (0.2 M HCl (pH 2.7) [66,91], or supersaturated blood plasma (SBF, pH 7.4) [88], at a liquid to surface area ratio of 4.424 mL cm −2 [87,88,92,93], under static conditions. A third liquid (TRIS buffered water, 1 M Tris-HCl, pH 4.0) was included to represent a buffered acidic environment, in the reported pH range of resorbing osteoclasts in vivo [66,94]. The liquid was refreshed every seven days, and discs were positioned in 50 mL centrifuge tubes to minimize surface contact with the tube, as described in [87].…”

Evidence for excessive osteoclast activation in SIRT6 null mice

“…Osteoporosis could be developed by either insufficient bone formation or excessive bone resorption, which corresponds to retarded osteoblast or hyperactive osteoclast, respectively 1 , 2 , 5 . Thus, the hyperactive osteoclast activation is critical for the development of osteopenia 3 , 6 , 7 .…”