case western reserve university





Charles J. Malemud, Ph.D.


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.

Dept. of Anatomy | 10900 Euclid Ave. | Cleveland, Ohio 44106-4930 | Phone:216.368.2433|
2004 Case Western Reserve University | Cleveland, Ohio 44106 | 216.368.2000 | legal notice