Biology Reference
In-Depth Information
8.2.2.2 Role of RANK, RANKL and OPG
As indicated in Sect.
8.2.2.1
, molecules like RANKL and RANK play an important
role in the generation of osteoclasts (Khosla
2001
). RANKL is expressed by the
bone lining cell and its ligand RANK by the mononuclear precursor. Following the
initial attachment mediated by ICAM-1/LFA-1 the synthesis of RANKL and
RANK is induced. In the microenvironment created by the close interaction of
the two cell types, RANKL and RANK bind to each other which results in a series
of intracellular signaling activities that steer the mononuclear cell in the direction of
the osteoclast (Teitelbaum
2007
). This transition is characterized by a sequence in
the expression of different molecules like NFAT, DC-STAMP, cathepsin K, calci-
tonin receptor, and TRACP. Several of these proteins (e.g., TRACP, calcitonin
receptor, cathepsin K) are relatively unique for the osteoclast. The RANKL-
mediated osteoclastogenesis is blocked by the ligand OPG. OPG is produced by
the bone lining cells; it binds to RANKL and prevents thereby RANKL-RANK
interaction. In this way OPG plays an essential role in limiting formation of
osteoclasts; high expression results in a low number of osteoclasts, whereas low
expression promotes osteoclastogenesis (Yasuda et al.
1998
).
When the mononuclear precursor has been transformed into a mononuclear
osteoclast that expresses enzymes like cathepsin K and TRACP, it induces the
withdrawal of the bone lining cell (Perez-Amodio et al.
2004
). This process of
withdrawal not only does make space for the osteoclast at the bone surface to attach
to, but also pin points the site where resorption is needed.
8.2.3 Preparation of the Bone Surface Prior to Osteoclastic
Resorption
8.2.3.1 Resorption of Collagen Fibrils by Bone Lining Cells
During the process of withdrawal from the bone surface the non-mineralized
components like collagen fibrils that still protrude from the surface have to be
removed (Chambers and Fuller
1985
); the osteoclast attaches to the mineral com-
ponent of the bone surface. Removal of these proteins by mammalian collagenase
was shown to induce attachment of the osteoclast and subsequent resorption
(Chambers et al.
1985
); without this cleaning activity osteoclasts do not or hardly
adhere to the bone surface. In subsequent ultrastructural studies the digestion of the
collagen fibrils protruding from the surface was shown to involve engulfment of
these fibrils by cytoplasmic extensions of the bone lining cell (Everts et al.
2002
;
Takahashi et al.
1986a
,
b
) (Fig.
8.1
). Digestion of the fibrils at this site proved
indeed to be metalloproteinase (MMP)-dependent (Everts et al.
2002
), a class of
enzymes that includes the collagenases. Although the exact MMP involved in this
cleaning process has not been elucidated yet, several findings suggest a role for
