Abstract
Prolonged critically ill patients present with distinct alterations in calcium and
bone metabolism. Circulating bone formation markers are reduced and bone resorption
markers are substantially elevated, indicating an uncoupling between osteoclast and
osteoblast activity, possibly resulting in pronounced bone loss, impaired traumatic
or surgical fracture healing, and osteoporosis. In addition, we have previously shown
that increased circulating osteoclast precursors in critically ill patients result
in increased osteoclastogenesis in vitro, possibly through FcγRIII signaling. In the current study, we investigated the effects
of sustained critical illness on bone metabolism at the tissue level in a standardized
rabbit model of prolonged (7 days), burn injury-induced critical illness. This in vivo model showed a reduction in serum ionized calcium and osteocalcin levels, as is seen
in humans. Trabecular area, bone mineral content, and density were decreased in sick
rabbits [by 43% (p<0.01), 31% (p<0.01), and 29% (p<0.05), respectively], as was the
trabecular gene expression of osteoblast and angiogenesis markers, indicating decreased
bone formation and impaired vascularization. There was no change in the expression
of osteoclast differentiation markers from the canonical RANK/RANKL/OPG pathway, however,
there was an increase in expression of markers from the non-canonical, immunoreceptor
tyrosine-based activation motif (ITAM) signaling pathway, FcγRIII, and DAP12 (148%
and 59%, respectively; p<0.01). The current study has shown a detrimental effect of
prolonged critical illness on trabecular bone integrity, possibly explained by reduced
osteoblast differentiation and angiogenesis, coupled with increased osteoclastogenesis
signaling that may be mediated via the non-canonical immunoreceptor tyrosine-based
activation motif signaling pathway.
Key words
intensive care unit - bone hyperresorption - osteoclast - osteoblast - ITAM
