Stephen Sims
Professor
 |
PH.D. McMaster University |
Scanning electron
micrograph shows resorption pits caused by the action of osteoclasts
resorbing the mineral substrate. We use a combination
of experimental methods, including digital fluorescence imaging using Ca2+-sensitive
fluorescent dyes to monitor regional changes of calcium in muscle and bone
cells. We also carry out patch clamp
recording to monitor membrane currents and their regulation. Osteoclasts are large multinucleated cells with extensive
lamellipodia. Understanding the cell biology of osteoclasts is essential for the
rational development of therapies directed at arresting the loss of bone in
inflammatory and metabolic diseases of bones and joints. The studies have relevance to understanding osteoclast activity in
diseases such as rheumatoid arthritis, where osteoclasts are found at the
pannus/bone interface and are responsible for loss of subchondral and
periarticular bone. The destruction of
bone and calcified cartilage contributes to the pain, progressive deformity and
disability associated with this disease.
Ion channels and receptors on osteoclasts represent targets for
intervention in diseases such as rheumatoid arthritis. Trainees under his supervision have won local, national and
international awards for their research, and have progressed to independent
careers in academia, education, medicine, dentistry and financial markets.
Dr. Sims is a cellular physiologist with expertise in ion channels and
signaling in skeletal and muscle cells.
Just as knowledge of ion channels and [Ca2+]i is
essential for understanding the physiology and pathology of nerve and muscle,
such information is instrumental for understanding control of osteoclasts, the
cells responsible for the resorption of bone.
Proposed
mechanism of LPA signaling in osteoclasts. LPA is released by neighboring osteoblasts
and binds to LPA receptors on an osteoclast. Binding of LPA to LPA1 activates receptor
to induce elevation of cytosolic free calcium, activation of NFAT and
enhancement of survival. Binding of LPA also causes cytoskeletal changes. This research was originally published in The Journal of Biological
Chemistry. Lapierre et al.
Lysophosphatidic acid signals through multiple receptors in osteoclasts to
elevate cytosolic calcium concentration, evoke retraction, and promote cell
survival. J Biol Chem. 2010; 285,
25792-25801. © the American
Society for Biochemistry and Molecular Biology. doi: 10.1074/jbc.M110.109322.
Lapierre DM,
Tanabe N, Pereverzev A, Spencer M, Shugg RP, Dixon SJ, Sims SM. Lysophosphatidic acid signals through multiple receptors
in osteoclasts to elevate cytosolic calcium concentration, evoke retraction and
promote cell survival. Journal of
Biological Chemistry 285: 25792-25801, 2010. Durand M,
Boire G, Komarova SV, Dixon SJ, Sims SM,
Harrison RE, Nabavi N, Maria O, Manolson MF, Mizianty M, Kurgan L, de
Brum-Fernandes AJ. The increased ex vivo osteoclastogenesis in patients with
rheumatoid arthritis is due to increased number of precursors and decreased
apoptosis - the in vitro osteoclast differentiation in arthritis (IODA) study. Bone.
48: 588-596, 2011. Espinosa-Tanguma R, O’Neil C, Chrones T, Pickering JG, Sims SM. Essential role for calcium
waves in migration of human vascular smooth muscle cells. American Journal of Physiology (Heart and Circulation) 301: H315-H323,
2011. Tanabe N,
Wheal BD, Kwon J, Chen HH, Shugg RPP, Sims
SM, Goldberg HA, Dixon SJ. Osteopontin signals through calcium-NFAT in
osteoclasts: a novel RGD-dependent pathway promoting cell survival. Journal of Biological Chemistry. 286: 39871-39881, 2011. Zhang T, Lu X,
Li J, Chidiac P, Sims SM, Feng Q.
Inhibition of Na/K ATPase promotes myocardial tumor necrosis factor-alpha
protein expression and cardiac dysfunction via calcium/mTOR signaling in
endotoxemia. Basic Research in Cardiology
107: 254-266, 2012. Durand M,
Komarova SV, Bhargava A, Li K, Fiorino C, Nabavi N, Manolson MF, Harrison RE,
Dixon SJ, Sims SM, Mizianty MJ,
Kurgan L, Boire G, Lucena-Fernandes M, de Brum-Fernandes A. Monocytes from
patients with osteoarthritis display increased osteoclastogenesis and bone
resorption: the in vitro osteoclast differentiation in arthritis (IODA) study.
MS ID# ar-11-1887. Arthritis and
Rheumatism. Oct 8. doi: 10.1002/art.37722. [Epub ahead of print] 2012. Sims SM, Panupinthu N, Lapierre DM, Pereverzev A, Dixon SJ.
Lysophosphatidic acid: a potential mediator of osteoblast-osteoclast signaling
in bone. Biochimica et Biophysica Acta.
1831: 109-116, 2013.
