SOUTHAMPTON, UK, and CORONA, Spain—Mitochondria, which may be remnants of ancient intracellular stow-aways, are emerging as power players in osteoarthritis (OA). New research reported in Arthritis & Rheumatism shows that mitochondrial respiratory chain dysfunction increases production of prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2); that antioxidants, vitamin E, and inhibitors of mitonchondrial calcium (Ca2+) and NF-κB can block this effect; and that certain mitochondrial DNA haplotypes provide significant protection against knee OA.^1,2

In an editorial commenting on the new recognition that our tiny intracellular energy generators are implicated in OA, Helmtrud I. Roach, PhD, of the bone and joint research group at the University of Southampton, UK, said, “[T]he study by Cillero-Pastor et al makes an important contribution and reminds the research community not to overlook the tiny mitochondria.”³

Mitochondrial respiratory chain dysfunction now prime suspect in OA pathogenesis

Dr. Roach noted that the new research highlights the key role played by degradative proteases such as matrix metalloproteases and aggrecanases. The source for these may be inflamed synovium or abnormal production by OA chondrocytes. Abnormal proteases are stimulated by inflammatory cytokines, but Dr. Roach said that the new evidence suggests that increased prostaglandin production may occur independently of cytokine activation. The study by Berta Cillero-Pastor et al showed that inhibiting the mitochondrial respiratory chain (MRC, complexes III and V) increased ROS (reactive oxygen species) which activated NF-κB. This increased expression of COX-2 and led to greater synthesis of PGE2.

“Until recently, altered mitochondrial respiratory function has received little attention, although impairment of mitochondrial ATP synthesis, in particular by NO [nitric oxide], was recognized as a process that compromises cell function and increases matrix calcification. It is also well known that if mitochondrial damage is such that cytochrome C is released, apoptosis of the chondrocyte will result,” Dr. Roach said.

Cillero-Pastor et al also identified NF-κB as an intermediary between ROS release from mitochondria and transactivation of COX-2.¹ They studied the role of MRC dysfunction in the inflammatory response of normal human chondrocytes, and used antimycin A and oligomycin to inhibit MRC complexes III and V respectively. The result was a significant increase in the levels of PGE2 and the expression of COX-2 at both the mRNA and protein levels. The researchers also found that antimycin A and oligomycin increased the levels of ROS. Antioxidants, vitamin E, and inhibitors of mitochondrial CA2+ and NF-κB also inhibited production of PGE2 and expression of COX-2.

“The response to blockers of mitochondrial Ca2+ movement showed that ROS production was dependent on mitochondrial Ca2+ accumulation,” the authors wrote. “These results strongly suggest that, in human chondrocytes, the inhibition of complexes III and V of the MRC induces an inflammatory response, which could be especially relevant in relation to PGE2 production via mitochondrial Ca2+ exchange, ROS production, and NF-κB activation. These data may prove valuable for a better understanding of the participation of mitochondria in the pathogenesis of OA.” They conclude that that mitochondrial dysfunction “induces an inflammatory response that could be especially relevant to the expression and synthesis of COX-2 and PGE2, thus playing a key role in OA pathogenesis.”

In the same issue of Arthritis & Rheumatism Ignacio Rego-Pérez, MD, and colleagues linked knee OA to differences in mitochondrial DNA (mtDNA).² These investigators found that knee OA prevalence and severity differ according to mtDNA haplotype. They analyzed mtDNA haplotypes in 457 patients with knee OA and 262 radiologically normal controls. They found that people carrying haplogroup J had less than half the risk of developing knee OA of individuals with other haplotypes, and if OA did develop, it had less severe progression.

OA thus joins other areas of anti-aging research currently focused on maintaining mitochondrial function as a key element in sustaining normal function. More research attention to dietary supplementation with antioxidants and with ubiquitin (co-enzyme Q10) is likely.

References

1. Cillero-Pastor B, Caramés B, Lires-Deán M, et al. Mitochondrial dysfunction activates cyclooxygenase 2 expression in cultured normal human chondrocytes. Arthritis Rheum. 2008;58:2409-2419.
2. Rego-Perez I, Fernandez-Moreno M, Fernandez-Lopez C. Mitochondrial DNA haplogroups. Role in the prevalence and severity of knee osteoarthritis. Arthritis Rheum. 2008;58:2387-2396.
3. Roach HI. The complex pathology of osteoarthritis: even mitochondria are involved (editorial). Arthritis Rheum. 2008;58:2217-2218.