Cartilage metabolism, mitochondria, and osteoarthritis

Introduction

Osteoarthritis continues to be a debilitating joint disease ultimately requiring joint replacement in most patients. OA (osteoarthritis) involves deterioration of the load-bearing cartilage, inflammation of the synovium, and structural changes in the underlying bone. The chondrocytes of articular cartilage are responsible for maintaining and repairing the tissue, and in OA these cells commonly fail in these important tasks.

Mitochondria are sub-cellular organelles that are involved in energy metabolism. Energy metabolism is important because it involves the conversion of chemical energy (e.g. glucose) into both ATP as well as the precursors to amino acids that are needed to maintain and repair cartilage.

Mitochondria host many of the enzymes involved in oxidative metabolism of glucose. Mutations in mitochondrial DNA result in functional differences between subgroups of patients containing distinct mitochondrial haplogroups. Recent studies show that different haplogroups have different susceptibility to OA. Here, we will review these haplogroups and discuss their relevance to cartilage repair in OA.

Mitochondrial Haplogroups

Mitochondrial variants are defined as individual groups characterized by the presence of a particular set of SNPs (single nucleotide polymorphisms), in the mitochondrial DNA (mtDNA) sequence, that were accumulated sequentially along radiating maternal lineages. Among individuals of Caucasian ancestry, 95% of the population belongs to one of the following haplogroups: H, I, J, T, U, K, V, HV*, W or X.¹ mtDNA haplogroups are related groups of mtDNAs characterized by stable polymorphic sites in mtDNA coding and non-coding regions that were shaped by natural selection as humans migrated north into colder climates. Specifically, European mtDNA haplogroups would also be expected to have been influenced by cold selection because of the episodic periods of cold associated with the repeated continental glaciations.

There is evidence about the importance of mtDNA haplogroups for energy production, and they show differences in their Oxidative Phosphorylation System (OXPHOS) coupling efficiency. Furthermore, an increasing number of studies show associations between some of the mtDNA haplogroups and multifactorial diseases.² In this sense, one haplogroup may be linked to susceptibility to energy deficiency diseases, but also be protective for degenerative diseases and aging. The explanation for this question is related to the multifunctional nature of the mitochondrion: the OXPHOS system both oxidizes dietary carbohydrates and fats with the oxygen we breathe to generate energy in the form of adenosine triphosphate (ATP) and thereby generates heat to maintain our body temperature by a mechanism called coupling efficiency. Tightly coupled OXPHOS would produce maximum ATP and minimum heat, whereas partially uncoupled OXPHOS would generate more heat and less ATP.

Mitochondrial DNA variation has been implicated in different neurodegenerative and metabolic disorders, including recently in osteoarthritis (OA). In terms of prevalence, European mtDNA haplogroup J and cluster JT have been significantly correlated with a decreased risk of knee OA in a Spanish cohort of subjects.³ This association was further replicated in an updated Spanish cohort of hip OA including 550 cases and 505 healthy controls.⁴ The mtDNA haplogroup T has been associated with a lower risk of knee OA in a population from the United Kingdom.⁵ In addition to the Caucasian mtDNA haplogroups J and T, the Asian mtDNA haplogroup B appeared to be a protective factor against knee OA in a population from China.⁶ The subsequent meta-analysis including data from Spain, USA (OAI), and the Netherlands (CHECK) confirmed the association of the haplogroup T and the mtDNA cluster JT with a lower risk of radiographic knee OA progression over time.⁷ Finally, a recent replication study and meta-analysis of 3217 subjects showed that the mtDNA haplogroup J is significantly associated with a lower rate of incident knee OA over an 8 year period.⁸

Mitochondrial diseases typically involve functionally degrading mutations to respiratory proteins, compared with the differential function associated with the various mtDNA haplogroups. The presentation of mitochondrial disease is heterogeneous and diverse, and they have very low prevalence.⁹ Although there have been findings of delayed growth in pediatric mitochondrial disease patients,¹⁰ we could not find evidence of associations between mitochondrial disease and osteoarthritis, perhaps due to the low prevalence of mitochondrial disease in the general population.

Metabolism and Relationship to Tissue Repair

Central metabolism involves the breakdown of glucose into carbon and associated biochemical energy by three main intracellular pathways. The primary pathways are glycolysis, the pentose phosphate pathway, and the TCA (tricarboxylic acid) cycle which includes OXPHOS through mitochondria. Glycolysis typically occurs within the cytoplasm using glucose imported from glucose transporters. The TCA cycle occurs within mitochondria, and the mitochondrial haplogroups involve mutations in mitochondrial proteins in the respiratory chain. The TCA cycle is important because it both generates substantial ATP and the precursors to several amino acids that are needed to maintain tissues such as articular cartilage, ligament, tendon, and bone.

To maintain tissue, musculoskeletal cells require amino acids. In order to synthesize amino acids, precursors are needed. Several of these precursors are synthesized within the TCA cycle. The TCA cycle involves more than twenty enzymes and utilizes acetyl coenzyme A as the product of glycolysis. Within the TCA cycle, precursors for the metabolism of several amino acids including arginine, alanine, aspartate, glutamate, and tyrosine are formed.

Collagen is a structural component of many musculoskeletal tissues. Hydroxyproline is a modified amino acid that is a major component of collagen, and is derived from ascorbate. Ascorbate metabolism begins from the TCA metabolite 2-oxoglutarate. Through central metabolism, ascorbate production is enabled through TCA activity, which is required to produce hydroxyproline for collagen.

The TCA cycle also generates NADH as a key input to the respiratory chain. Mitochondrial haplogroups are defined by mutations within respiratory chain proteins NADH dehydrogenase (Complex I), Cytochrome b (Complex III), Cytochrome oxidase (Complex IV), and ATP synthase. The single nucleotide polymorphisms (SNPs) that comprise distinguish mtHaplogroups likely drive differences in enzymatic activity. These activity differences may then drive functional differences in redox balance (e.g. differential NADH production) and synthesis of amino acid precursors that contribute to the variation in OA susceptibility between mtHaplogroups. Ongoing studies seek to elucidate these mechanisms to improve our understanding of the role of mtHaplogroups in OA.

Finally, mitochondrial function involves production of Reactive Oxygen Species (ROS). ROS can damage proteins and activate cell death pathways.¹¹ In vitro studies find that mitochondria from mtHaplogroup J appear to produce less free radicals and have increased survival compared with mtHaplogroup H.⁸

Future Directions

There is great clinical promise in further understanding the relevance of mtHaplogroups in osteoarthritis. Better understanding of the cellular mechanisms by which mtHaplogroups affect OA pathogenesis may yield patient-specific drug targets. Or, different haplogroups may require different physical therapy regimes after joint replacement.

Recent studies in vitro studies find that chondrocytes respond to compression with changes in central metabolites,¹² particularly within the TCA cycle.¹³ It remains unknown if specific mtDNA haplogroups can promote or constrain chondrocyte-driven cartilage repair and associated osteoarthritis susceptibility. Future studies examining relationships between mtDNA haplogroups and chondrocyte biology have the potential to identify patient-specific risk factors and treatments for osteoarthritis.