Mitochondrial quality control in cartilage damage and osteoarthritis: new insights and potential therapeutic targets.

Osteoarthritis (OA) is a multifactorial arthritic disease of weight-bearing joints concomitant with chronic and intolerable pain, loss of locomotion and impaired quality of life in the elderly population. Although the prevalence of OA increases with age, its specific mechanisms have not been elucidated and effective therapeutic disease-modifying drugs have not been developed. As essential organelles in chondrocytes, mitochondria supply energy and play vital roles in cellular metabolism, proliferation and apoptosis. Mitochondrial quality control (MQC) is the key mechanism to coordinate various mitochondrial biofunctions, primarily through mitochondrial biogenesis, dynamics, autophagy and the newly discovered mitocytosis. An increasing number of studies have revealed that a loss of MQC homeostasis contributes to the cartilage damage during the occurrence and development of OA. Several master MQC-associated signaling pathways and regulators exert chondroprotective roles in OA, while cartilage damage-related molecular mechanisms have been partially identified. In this review, we summarized known mechanisms mediated by dysregulated MQC in the pathogenesis of OA and latent bioactive ingredients and drugs for the prevention and treatment of OA through the maintenance of MQC.

Deficiency of hyaluronan synthase 1 (Has1) results in chronic joint inflammation and widespread intra-articular fibrosis in a murine model of knee joint cartilage damage.

OBJECTIVE: Articular cartilage defects commonly result from traumatic injury and predispose to degenerative joint diseases. To test the hypothesis that aberrant healing responses and chronic inflammation lead to osteoarthritis (OA), we examined spatiotemporal changes in joint tissues after cartilage injury in murine knees. Since intra-articular injection of hyaluronan (HA) can attenuate injury-induced osteoarthritis in wild-type (WT) mice, we investigated a role for HA in the response to cartilage injury in mice lacking HA synthase 1 (Has1(-/-)). DESIGN: Femoral groove cartilage of WT and Has1(-/-) mice was debrided to generate a non-bleeding wound. Macroscopic imaging, histology, and gene expression were used to evaluate naïve, sham-operated, and injured joints. RESULTS: Acute responses (1-2 weeks) in injured joints from WT mice included synovial hyperplasia with HA deposition and joint-wide increases in expression of genes associated with inflammation, fibrosis, and extracellular matrix (ECM) production. By 4 weeks, some resurfacing of damaged cartilage occurred, and early cell responses were normalized. Cartilage damage in Has1(-/-) mice also induced early responses; however, at 4 weeks, inflammation and fibrosis genes remained elevated with widespread cartilage degeneration and fibrotic scarring in the synovium and joint capsule. CONCLUSIONS: We conclude that the ineffective repair of injured cartilage in Has1(-/-) joints can be at least partly explained by the markedly enhanced expression of particular genes in pathways linked to ECM turnover, IL-17/IL-6 cytokine signaling, and apoptosis. Notably, Has1 ablation does not alter gross HA content in the ECM, suggesting that HAS1 has a unique function in the metabolism of inflammatory HA matrices.

Responses of leaf nitrogen and mobile carbohydrates in different Quercus species/provenances to moderate climate changes.

Global warming and shortage of water have been evidenced in the recent past and are predicted for the future. Climate change will inevitably have considerable impact on plant physiology, growth, productivity and forest ecosystem functions. The present study determined the effects of simulated daytime air warming (+1 to 1.5 °C during the growing season), drought (-40% and -57% of mean precipitation of 728 mm during the 2007 and 2008 growing season, respectively) and their combination, on leaf nitrogen (N) and non-structural carbohydrates (NSC) of two Quercus species (Q. robur and Q. petraea) and provenances (two provenances for each species) grown in two soil types in Switzerland across two treatment years, to test the hypothesis that leaf N and NSC in the more water-sensitive species (Q. robur) and provenances (originating from water-rich locations) will more strongly respond to global warming and water deficit, compared to those in the more drought-tolerant species (Q. petraea) or provenances. No species- and provenance-specific responses in leaf N and NSC to the climate treatment were found, indicating that the results failed to support our hypothesis. The between-species variation of leaf N and NSC concentrations mainly reflected differences in biology of the two species, and the between-provenance variation of N and NSC concentrations apparently mirrored the climate of their origins. Hence, we conclude that (i) the two Quercus species studied are somewhat insensitive, due to their distribution covering a wide geographical and climate range, to moderate climate change within Switzerland, and (ii) a moderate global warming of B1 scenario (IPCC 2007) will not, or at least less, negatively affect the N and carbon physiology in Q. robur and Q. petraea.