NASA Human Research Program Investigators' Workshop (2012)
4258.pdf
EXTRACELLULAR MATRIX REGULATES BIOAVAILABILITY OF PROINFLAMMATORY
CYTOKINES INFLUENCING BONE FORMATION.
J.R.T. Oxford1, R. Ryan1, L. Mellor1,C.J. Jorcyk1, T.T. Rohn1, and K.A. Mitchell1
1
Department of Biological Sciences, Biomolecular Research Center, 1910 University Drive, Boise ID, 83725
Joxford@boisestate.edu.
INTRODUCTION
Identification of molecular targets that modulate the mechanosensory signaling pathways is necessary for the
development of new and novel countermeasures to bone loss experienced by astronauts. Current knowledge
indicates that the balance between the bone building effects of osteoblasts and the bone resorbing effects of
osteoclasts is responsible for homeostasis and the maintenance of healthy bone mass. When mechanical forces
experienced by the cells of the skeleton are altered as in the case of space flight, this balance is disrupted. Currently,
a gap exists in our knowledge of the cell signaling pathways that are responsive to mechanical load, and those that
coordinate balance between osteoblast and osteoclast function. Lack of knowledge about cellular responses to
mechanical load is a problem because it limits the development of countermeasures that would allow the
maintenance or reestablishment of skeletal homeostasis. The knowledge and technologies gained through this
research could also help those on Earth suffering from osteoporosis and related bone diseases.
We hypothesize that microgravity alters bone homeostasis by mechanisms that are dependent upon molecules of the
extracellular matrix mediating signaling pathway(s) that influence osteoblast differentiation. This effect is predicted
to modulate the expression of mediators of osteoblast-dependent osteoclastogenesis as well. We have focused on
Oncostatin M (OSM) and extracellular matrix molecules in bone homeostasis. OSM is a member of the pleiotropic
IL-6 cytokine family with demonstrated roles in bone organogenesis, differentiation, and regeneration, and is a
candidate for mediation of osteoblast-dependent osteoclastogenesis.
RESULTS
Microarray studies indicate that expression of extracellular matrix molecules and proinflammatory cytokines were
among those genes altered by modeled microgravity [1]. Col11a1 expression level was decreased, with respect to
culture conditions at 1xg. Minor fibrillar collagens and other molecules of the extracellular matrix can modulate the
bioavailability of proinflammatory cytokines such as OSM, the production of which increases immediately after
microgravity exposure by modeled microgravity.
DISCUSSION AND CONCLUSIONS
Osteoblast function is modulated under microgravity conditions, and changes in actin and tubulin cytoskeleton have
been reported in cells exposed to microgravity [2]. Microgravity increases the production and secretion of
inflammatory cytokines by monocytes and macrophages in the extracellular matrix [3], and may affect cytokine
production by osteoblasts, inducing both autocrine and paracrine pathways. The production of proinflammatory
cytokines is a key step in promoting bone destruction as osteoblasts are highly responsive to cytokines [4]. Minor
fibrillar collagens are candidates for mediation of bone morphogenetic protein and Wnt signaling pathways in
osteoblasts with modulation of mineralization through interaction with regulatory proteins. Additionally, minor
fibrillar collagens may also modulate the bioavailability of proinflammatory cytokines such as OSM.
REFERENCES
[1] Genome Expression Omnibus N.(2010) [2] Kumei Y, Morita S, Katano H, Akiyama H, Hirano M, Oyha K,
Shimokawa H. (2006) Microgravity Signal Ensnarls Cell Adhesion, Cytoskeleton, and Matrix Proteins of Rat
Osteoblasts: Osteopontin, CD44, Osteonectin, and α-Tubulin. Annals of the New York Academy of Sciences 1090,
311-317. [3] Chapes SK, Morrison DR, Guikema JA, Lewis ML, Spooner BS. (1992) Cytokine secretion by
immune cells in space J. Leukoc. Biol. 52, 104-110. [4] Scheidt-Nave C, Bismar H, Leidig-Bruckner G, Woitge H,
Seibel MJ, Ziegler R, Pfeilschifter J. (2001) Serum interleukin 6 is a major predictor of bone loss in women specific
to the first decade past menopause. J Clin Endocrinol Metab 86, 2032-42.