Mitochondrial DNA haplogroups influence the risk of incident knee osteoarthritis in OAI and CHECK cohorts. A meta-analysis and functional study

Abstract

Objective To evaluate the influence of the mitochondrial DNA (mtDNA) haplogroups in the risk of incident knee osteoarthritis (OA) and to explain the functional consequences of this association to identify potential diagnostic biomarkers and therapeutic targets. Methods Two prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 2579 subjects of the incidence subcohort, and the cohort hip and cohort knee (CHECK) included 635, both with 8-year follow-up. The analysis included the association of mtDNA haplogroups with the rate of incident knee OA in subjects from both cohorts followed by a subsequent meta-analysis. Transmitochondrial cybrids harbouring haplogroup J or H were constructed to detect differences between them in relation to physiological features including specific mitochondrial metabolic parameters, reactive oxygen species production, oxidative stress and apoptosis. Results Compared with H, the haplogroup J associates with decreased risk of incident knee OA in subjects from OAI (HR=0.680; 95% CI 0.470 to 0.968; p<0.05) and CHECK (HR=0.728; 95% CI 0.469 to 0.998; p<0.05). The subsequent meta-analysis including 3214 cases showed that the haplogroup J associates with a lower risk of incident knee OA (HR=0.702; 95% CI 0.541 to 0.912; p=0.008). J cybrids show a lower free radical production, higher cell survival under oxidative stress conditions, lower grade of apoptosis as well as lower expression of the mitochondrially related pro-apoptotic gene BCL2 binding component 3 (BBC3). In addition, J cybrids also show a lower mitochondrial respiration and glycolysis leading to decreased ATP production. Conclusions The physiological effects of the haplogroup J are beneficial to have a lower rate of incident knee OA over time. Potential drugs to treat OA could focus on emulating the mitochondrial behaviour of this haplogroup.

Mitochondrial DNA haplogroups and ageing mechanisms in osteoarthritis

“…In the presence of staurosporine, which induces cell apoptosis, the cybrids with the haplogroup H had over 50% more apoptotic cells than the cybrids with the low OA risk haplogroup J 7. These data, therefore, prove the functional relevance of mtDNA variation linked to risk of OA on cell function and survival and is in agreement with recent work by the same group showing that OA cartilage exhibits signs of early molecular ageing compared with healthy age-matched cartilage 2…”

“…The mtDNA haplotypes T, J and the JT cluster, on the other hand, are significantly associated in populations from the USA, the Netherlands and Spain with radiographic incidence and progression of the disease7 15 (table 1). Fernandez-Moreno and coauthors report that the mtDNA haplogroup J, the same haplogroup associated with lower OA prevalence, lower disease progression and lower cartilage loss, is also associated with a significantly lower risk of incident knee OA in a population of 3124 individuals from two prospective cohorts from the Netherlands and the USA 7…”

“…To answer this question, Fernandez-Moreno et al 7 used cytoplasmic hybrid (cybrid) cell lines. Cybrids incorporate mitochondria from human subjects and perpetuate the mtDNA-encoded components while maintaining the nuclear background of different cybrid lines as constant 16.…”

Differential Association of Mitochondrial DNA Haplogroups J and H With the Methylation Status of Articular Cartilage: Potential Role in Apoptosis and Metabolic and Developmental Processes

“…The relationship between mtDNA haplogroups and apoptosis is not a new discovery; a study by Kenney et al showed that cybrids with haplogroup J had reduced expression of apoptosis‐related genes compared to cybrids with haplogroup H . In addition, cybrids with haplogroup J also show a lower grade of apoptosis under stress conditions as well as a lower expression of the apoptotic gene BBC3 than cybrids with haplogroup H . Taken together, these findings indicate that inherited mitochondrial variants can affect apoptosis pathways and, since chondrocyte death is a central feature in OA progression , this could explain, at least in part, the associations of haplogroup J with a lower rate of knee and hip OA prevalence and incident knee OA .…”

“…Specifically, the mtDNA haplogroups influence the prevalence of OA in different geographic populations and have been shown to affect radiographic progression and cartilage integrity over time in patients in the progression subcohort of the Osteoarthritis Initiative . A recent meta‐analysis involving >3,000 subjects concluded that mtDNA haplogroups significantly influence the rate of incident knee OA; specifically, those subjects harboring haplogroup J had a significantly decreased risk of developing incident knee OA at 8 years compared to subjects harboring haplogroup H, which differs in terms of reactive oxygen species and ATP production, mitochondrial metabolism, and apoptosis .…”