Background In the last years the study of the mitochondria in the context of osteoarthritis (OA) attracted much attention. In the present work we aim to analyze the role of the mtDNA haplogroups in the development of incident knee OA in well-characterized study cohorts
Objectives To analyze the influence of the mtDNA haplogroups in the rate of incident knee OA in the prospective cohorts of CHECK and OAI and to perform functional analysis with transmitochondrial cybrids to explore the consequences of the mitochondrial background in the pathogenesis of Osteoarthritis
Methods The influence of the haplogroups in the development of incident knee OA at eight years in 2579 subjects from the Osteoarthritis Initiative (OAI) and 635 subjects from the Cohort hip and Cohort knee (CHECK) was assessed. A subsequent meta-analysis was conducted to strengthen the association of these individual studies.
Transmitochondrial cybrids carrying the haplogroups J and H were constructed to study the influence of the mitochondrial background in different OA-related features.
Results The haplogroup J significantly associates with a decreased risk of incident knee OA in subjects from the OAI (HR=0.680;95%CI=0.470–0.968;p<0.05) and CHECK (HR=0.728;95%CI=0.469–0.998;p<0.05). The subsequent meta-analysis including 3214 cases showed that the haplogroup J significantly associates with a lower risk of incident knee OA (HR=0.702;95%CI=0.541–0.912;p=0.008) (Figure 1).
Compared with the haplogroup H, haplogroup J shows a lower free radical production, specially peroxide/peroxynitrite (52.51±11.34 vs 41.26±7.48;p<0.05) and superoxide (8.58±3.0 vs 4.25±0.9;p<0.05), a higher cell survival under oxidative stress conditions (29.63±3.3 vs 56.45±7.36;p<0.05), a lower grade of apoptosis (7.35±3.78 vs 4.69±1.68;p<0.05) as well as a lower expression of the mitochondrially-related pro-apoptotic gene BBC3 (3.3-fold;p<0.05), a higher lactate production (64.22±10.76mg/dl vs 51.42±6.85mg/dl;p<0.05) and a lower expression of the mitochondrial biogenesis-related gene PGC1-α (2-fold;p<0.05)
Conclusions The haplogroup J reduces the risk of incident knee OA. This mitochondrial variant constitute a protective phenotype against the development of OA, emerging as a powerful OA biomarker and even leading to the consideration of the mitochondrion as a potential therapeutic target in OA
Acknowledgement We'd like to acknowledge to the participants of CHECK and OAI cohorts
Disclosure of Interest None declared