Profilaksa DVT kod velikih ortopedskih operacija - Depol ...

20 - 22 September 2012, Opatija, Croatia
OSTEOPOROSIS: COMMON FEATURE UNDERLINED BY
DIFFERENT PATHOGENETIC MECHANISMS
Danka Grčević, University of Zagreb School of Medicine, Zagreb, Croatia
The misbalance in the differentiation and activity of principal bone cells, bone forming osteoblasts and bone
resorbing osteoclasts, leads to osteoporosis, characterized by the loss of bone mass and increased risk of fragility
fractures. There are multiple pathogenetic mechanisms underlying osteoporosis, involving not only the osteoblastic
and osteoclastic cell lineages but also other bone-marrow cells, systemic hormones, local cytokines,
and growth factors. The RANKL/RANK interaction is critical for osteoclastogenesis and hence represents a final
common pathway for any pathogenetic factor in osteoporosis that acts by increasing osteoresorption. By using
different mouse models, we investigated several aspects of the disease mechanism, addressing both bone formation
and bone degradation. We used genetic mutation causing the osteogenesis imperfecta murine (OIM),
to confirm that the osteoblastic lineage is under continuous stimulation, but with decreased ability for maturation.
Moreover, immature osteoblasts strongly support osteoclastogenesis, through higher RANKL/OPG ratio and
TNF-alpha expression. In view of the reports that human postmenopausal osteoblasts constitutively express Fas
and our finding that Fas receptor activation directly inhibits osteoblast differentiation, we confirmed that Fas/FasL
system has an important role in the pathogenesis of postmenopausal osteoporosis by mediating apoptosis and
inhibiting differentiation of osteoblast lineage cells. Inflammatory processes alter the bone microenvironment to
promote irreversible bone destruction. In pathologic states, activated T-lymphocytes produce RANKL and other
proresorptive cytokines playing a role in osteoporosis as well as inflammation-induced bone loss. In the model of
systemic inflammation, by endotoxin administration, and autoimmune reaction, in collagen-induced arthritis, we
confirmed that there is a decrease in total bone mass mediated by increased number of identified bone-marrow
and peripheral osteoclast progenitors and their enhanced activity maintained by proinflammatory factors. Finally,
we hypothesize that cells expressing smooth muscle alpha-actin promoter (aSMA)-directed transgene represent
mesenchymal progenitors of adult bone tissue and confirmed that aSMA+ cells serve as a pool of skeletal progenitors
with a potential for terminal differentiation into mature osteoblasts during fracture healing. Although
we identified a defined population of mesenchymal progenitors with the active role in bone regeneration, many
puzzles are still missing before we would be able to achieve the full therapeutic success in osteoporosis treatment.
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