Clinical and Technical Review - Tecomedical

Bone Resorption
Osteoclast:
Large motile, multinucleated bone cell located on bone surfaces.
Responsible for the resorption of bone matrix (osteoid).
Osteoclasts have a ruffled border of the cell membrane that
is surrounded by an organelle-free region, or « clear zone ».
Mineral Dissolution:
These processes take place beneath the ruffled border
and depend on lysosomal enzyme secretion and an acid
microenvironment. A pH gradient across the ruffled
membrane is the consequence of active transport
mechanisms by the osteoclasts.
Collagen degradation:
Osteoclasts actively synthesize lysosomal enzymes,
in particular the tartrate resistant isoenzyme of acid
phosphatase (TRAP 5b) and cysteine-proteinases such
as Cathepsin K that are capable of degrading collagen.
Two bone collagenolytic pathways exist:
1. A Cathepsin K collagen degradation pathway is the prevailing
one. Resulting in the following epitopes:
CTX, NTX, DPD and PYD.
2. A Matrix MetalloProteinase (MMP) collagen degradation
pathway resulting in the epitope ICTP. This pathway becomes
significant in some situations, including metastatic
bone diseases and multiple myeloma. ICTP however, has
proven to be a very poor marker in osteoporosis.
Proteins
TRAP 5b:
The active isoform of TRAP5b, serum band 5 tartrateresistant
acid phosphatase, is specifically synthesized
by bone-resorbing osteoclasts. It has been shown that
TRAP5b catalyzes the formation of reactive oxygen
species (ROS). Research results indicate that ROS
generated by TRAP5b are involved in the degradation
of bone matrix products in resorbing osteoclasts.
TRAP5b activity reflects the osteoclast activity and is associated
with the number of osteoclasts. TRAP5b is consideredamarkerfortherateofboneresorptionandmaybeof
particular importance for patients with renal failure because
- in contrast to other marker of resorption -
TRAP5b does not accumulate in the blood.
In tumor patients TRAP5b is an indicator for increased bone
resorption due to bone metastases. Changes in TRAP
activity during therapy monitoring allow the assessment of
the efficiency of antiresorptive therapies in osteoporotic
patients.
RANK:
Osteoclastic receptor for sRANKL, the main stimulatory factor
for the formation of mature osteoclasts.
Cathepsin K:
Main osteoclastic protease, responsible for bulk degradation
of Type I Collagen. Acts both intra- and extra-cellularly.
Lysosomal enzymes:
Enzymes secreted by the osteoclasts, responsible for
mineral dissolution in an acid environment.
MMP:
Matrix metalloproteinases MMP-2, -9, -13, -14 participate in
the degradation of the collagenous bone matrix,
resulting in epitope ICTP.
Calcitonin receptor:
Osteoclastic receptor for calcitonin, an inhibitor of
osteoclasts activity.
Sclerostin:
Sclerostin is the protein product of the SOST gene, which is
located at 17q12-21 and highly conserved across vertebrate
species.
The highest expression of sclerostin throughout the adult
skeleton has been observed in hypertrophic chondrocytes
and osteocytes. Sclerostin belongs to the DAN1 family of
glycoproteins of which multiple family members antagonize
bone morphogenetic protein (BMP) and/or Wnt2 activity.
Sclerostin blocks canonical Wnt signaling by binding to the
Wnt coreceptors LRP5/63 . Thus, it inhibits bone formation
by regulating osteoblast function and promoting osteoblast
apoptosis. By blocking the Wnt-pathway Sclerostin also
antagonises bone morphogenetic protein action e.g. osteoblast
differentiation, but does not inhibit direct BMP-induced
responses.
Sclerostin expression is down-regulated by Parathyroid hormone
(PTH) as well as the mechanical stimulation of bone
reduces the expression of sclerostin.
1 DAN = differential screening-selected gene aberrative in neuroblastomaa
2 Wnt = wingless Proteine
3 LRP = low-density lipoprotein receptor-related protein 5 and 6
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