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Charles J. Malemud, Ph.D.
ROLE OF CHONDROCYTE APOPTOSIS IN ARTHRITIS
Programmed
cell death (apoptosis) is characterized by a
sequence of intracellular events culminating in
cell death as follows:
-
An
initiating event via either receptor-mediated
ligand binding (extrinsic pathway) or via
changes in mitochondrial membrane structure
(intrinsic pathway) or both.
-
Formation of
death-inducing signaling complexes (DISCs) can
involve proteins such as FADD (Fas-activating
death domain protein) which result in
procaspase activation.
-
Mature
(activated) caspases which carry out the final
“executioner” signals resulting in DNA
fragmentation and cell death.
Our laboratory
focuses on an extrinsic apoptosis pathway
induced by hydrostatic pressure as well as
downstream intracellular signaling that result
in human chondrocyte death in vitro. As
cartilage repair after injurious pressure
generally requires that chondrocyte
proliferation and extracellular matrix synthesis
occur, the efficiency of cartilage repair can be
compromised by a loss in viable chondrocytes
through apoptosis. Chondrocyte apoptosis,
initiated by hydrostatic pressure in vitro,
also augments the transcription of
inflammatory cytokine genes such as tumor
necrosis factor-α, and nitric oxide synthase
which are known to be present in significant
quantities in arthritic synovial joints.
Selected References:
Islam S,
Kermode T, Sultana D, Moskowitz RW, Mukhtar H,
Malemud CJ, Haqqi TM (2001) Expression profile
of protein tyrosine kinase genes in human
osteoarthritis chondrocytes. Osteoarthritis
and Cartilage 9: 684-693.
Islam N, Haqqi
TM, Jepsen KJ, Kraay M, Welter JF, Goldberg VM,
Malemud CJ (2002) Hydrostatic pressure induces
apoptosis in human chondrocytes from
osteoarthritic cartilage through up-regulation
of tumor necrosis factor-α, inducible nitric
oxide synthase, p53, c-myc and bax-α and
suppression of bcl-2. Journal of Cellular
Biochemistry 87: 266-278.
Singh R, Ahmed
S, Malemud CJ, Goldberg VM, Haqqi TM (2003)
Epigallocatechin-3-gallate selectively inhibits
interleukin-1β-induced activation of mitogen
activated protein kinase subgroup
c-Jun-N-terminal kinase in human osteoarthritis
chondrocytes. Journal of Orthopaedic Research
21: 102-109.
Malemud CJ,
Islam N, Haqqi TM (2003) Pathophysiologic
mechanisms in osteoarthritis lead to novel
therapeutic strategies. Cells Tissues Organs
174: 34-48. |
