Publication: Structure and function of V-ATPases in osteoclasts: potential therapeutic targets for the treatment of osteolysis
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Date
2007
Authors
Xu, J. ; Cheng, T. ; Feng, H.T. ; Pavlos, N.J. ; Zheng, M.H.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Excessive activity of osteoclasts becomes
manifest in many common lytic bone disorders such as
osteoporosis, Paget’s disease, bone aseptic loosening and
tumor-induced bone destruction. Vacuolar proton pump
H+-adenosine triphosphatases (V-ATPases), located on
the bone-apposed plasma membrane of the osteoclast,
are imperative for the function of osteoclasts, and thus
are a potential molecular target for the development of
novel anti-resorptive agents. To date, the V-ATPases
core structure has been well modeled and consists of two
distinct functional domains, the V1 (A, B1, B2, C1, C2,
D, E1, E2, F, G1, G2, G3, and H subunits) and V0 (a1,
a2, a3, a4, d1, d2, c, c’ e1, e2 subunits) as well as the
accessory subunits ac45 and M8-9. However, the exact
configuration of osteoclast specific V-ATPases remains
to be established. Inactivation of subunit a3 leads to
osteopetrosis in both mice and man because of nonfunctional
osteoclasts that are capable of acidifying the
extracellular resorption lacuna. On the other hand,
inactivation of subunits c, d1 and ac45 results in early
embryonic lethality, indicating that certain subunits, such
as a3, are more specific to osteoclast function than
others. In osteoclasts, V-ATPases also cooperate with
chloride channel protein CLC-7 to acidify the resorption
lacuna. In addition, development of V-ATPases
inhibitors such as bafilomycin A1, SB 242784 and
FR167356 that selectively target osteoclast specific VATPases
remains a challenge. Understanding the subunits of V-ATPase regulate osteoclast function might
facilitate the development of novel and selective
inhibitors for the treatment of lytic bone disorders. This
review summarizes recent research developments in VATPases
with particular emphasis on osteoclast biology.
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