Osteoarthritis (OA) may be caused by hypometabolism-driven cholesterol accumulation; vitamin B5 mat treat it
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The role of mitochondria and oxidative metabolism in “structural” conditions such as OA is becoming more widely recognized every day. One of the reasons medicine has been reluctant to acknowledge the role of metabolism in such “structural” conditions is the fact that cartilage has a very poor blood supply, which (in theory) limits the effects of metabolism in such tissues. The study below demonstrates that mitochondria and its debris can accumulate even in such tissues with poor-blood flow resulting in local inflammatory reactions and tissue degradation over time. Interestingly, the study below demonstrates that one of the key causes of such mitochondrial dysfunction is accumulation of cholesterol in chondrocytes. Normally, cholesterol is metabolized into the mitochondria to produce steroids and seco-steroids (e.g. vitamin D). However, when mitochondrial function is low, cholesterol accumulates and causes mitochondrial damage and inflammation. One of the key factors in maintaining normal oxidative metabolism is the acetyl-CoA/CoA ratio. When that ratio is elevated, the NADH/NAD+ ratio also rises, Krebs Cycle activity declines and also inhibits the activity of the enzyme pyruvate dehydrogenase (PDH). This phenomenon of high acetyl-CoA/CoA and (mitochondrial) NADH/NAD+ ratio is the main mechanism behind the (in)famous Randle Cycle, that is now known to be involved in virtually all chronic conditions. Namely, excessive fatty acid oxidation (FAO) raises both of said ratios above, with subsequent decline in glucose oxidation, but also of Krebs Cycle activity and ultimately declining electron transport chain (ETC) activity as well, with the last portion responsible for more than 98% of the production of reactive oxygen species (ROS). Thus, a simple change in those ratios can wreak havoc on the entire metabolic cascade, which eventually translates into structural changes as well. While excessive FAO is one of the well-known causes of elevated acetyl-CoA/CoA ratio, another less-known reason is decline in the synthesis of CoA. This co-factor is synthesized from the precursor known as vitamin B5. While the most widely-used form of B5 is D-panthenol, a more direct CoA precursor is the closely-related substance known as pantethine. Interestingly, panthethine administration has been shown to normalize cholesterol levels in humans, with the main proposed mechanism being that increased CoA lowers the acetyl-CoA/CoA ratio, thus speeding up oxidative metabolism and thus cholesterol metabolism into downstream steroids and seco-steroids.
The study below is one of the first to demonstrate that OA may be entirely metabolic in origin, being driven by inflammation caused by cholesterol accumulation in the mitochondria due to low CoA levels. Conversely, the study demonstrated that simply supplementing with pantethine elevated CoA, reversed cholesterol accumulation into the mitochondria and largely reversed the symptoms of OA. The human-equivalent dose (HED) of pantethine was 10mg/kg orally daily for a period of 4-8 weeks. This dose is quite in line with the dose commonly administered in human studies, which is typically 600mg twice daily. In summary, simply administering a vitamin precursor of a crucial co-factor in oxidative metabolism was sufficient to reverse cholesterol accumulation, and reverse established OA pathology. Considering that cholesterol accumulation has been linked to a number of chronic conditions with an inflammatory component, the study below suggests that pantethine supplementation may be a viable intervention for those conditions as well. In corroboration, human studies with 600mg x 2 daily has been demonstrated to not only lower cholesterol, but also decrease multiple biomarkers of cardiovascular disease (CVD) and diabetes, including cholesterol, triglycerides, free fatty acids (NEFA), atheroma size, insulin levels, creatinine, blood urea nitrogen, etc.
https://www.nature.com/articles/s41467-025-65689-w
“…In fact, the pathogenesis of OA and many other diseases, such as cardiovascular and neurodegenerative diseases, is closely related to inflammation and metabolism, in which mitochondria play an important role57. Due to the dual regulatory role of mitochondria, understanding the mechanisms that regulate “metabolic-inflammatory” shift of mitochondria and its impact on disease progression is of great importance. To address this, we demonstrated that osteocyte mitochondria disrupt cholesterol metabolism in chondrocytes, with excessive cholesterol inducing osteocyte mitochondrial mPTP activation and mtDNA leakage, which shifts them toward an inflammatory phenotype. To further address the underlying mechanism, we identified pantetheine, an intermediate in the production of coenzyme A and closely related to cholesterol metabolism42,43, as being significantly decreased by osteocyte mitochondria. This depletion occurs because mitochondria directly degrade CoA, leading to pantetheine depletion. We also identified Nudt8, which is expressed in osteocyte mitochondria and degrades CoA, further regulating cholesterol homeostasis. The expression of Nudt8 drives osteocyte mitochondria toward an inflammatory phenotype during intercellular transfer. These characteristics of Nudt8 suggest it as a potential regulator of the “metabolic-inflammatory” balance in osteocyte mitochondria. However, we currently lack tools to specifically track mitochondrial-Nudt8-dependent regulation within chondrocytes in vivo. Further studies are required to validate Nudt8 as the phenotypic switch point of osteocyte mitochondria in vivo. Additionally, exploring other potential switch targets within mitochondria warrants further investigation. By targeting mitochondrial Nudt8 and its related metabolism, we treated chondrocytes with pantethine. Pantethine has been used for the treatment of hyperlipidemia, cardiovascular prevention, and in children with pantothenate kinase-associated neurodegeneration42,58. We performed oral treatment in different OA models and showed promising results. As it is one of the metabolites present in the human body, the safety and efficacy is reliable, though the delivery strategy of pantethine requires further study.”
Mitochondria-Cholesterol Link Worsens Osteoarthritis in Mice
“…In a groundbreaking study published in Nature Communications, researchers have unveiled a novel cellular mechanism by which mitochondria act as pivotal relay stations for cholesterol signals that exacerbate osteoarthritis in mice. This discovery sheds new light on the intricate molecular pathways that drive the progression of osteoarthritis, a debilitating joint disease characterized by cartilage degradation and chronic pain. The findings not only deepen our understanding of osteoarthritis pathophysiology but also open promising avenues for targeted therapeutic interventions aimed at mitigating disease advancement through modulating mitochondrial cholesterol signaling.”
“…At the core of this discovery lies the observation that cholesterol, traditionally viewed as a structural lipid and precursor of steroid hormones, can serve as a potent signaling molecule within mitochondria. These dynamic organelles integrate cholesterol signals to induce alterations in mitochondrial function and metabolic homeostasis. The researchers demonstrated that cholesterol accumulation in mitochondria triggers robust activation of pro-inflammatory and catabolic pathways, accelerating extracellular matrix breakdown and chondrocyte apoptosis—the death of cartilage cells essential for joint integrity.”
“…To dissect this mechanism, the research team employed a sophisticated array of molecular biology techniques, including mitochondrial isolation, lipidomic profiling, and gene expression analyses. They established that mitochondrial cholesterol levels directly correlate with the expression of enzymes and signaling molecules implicated in matrix degradation. Intriguingly, the study identified a previously unrecognized mitochondrial cholesterol sensor that modulates downstream inflammatory cascades. This sensor effectively translates lipid signals into biochemical actions that exacerbate osteoarthritic pathology.”
“…The animal model utilized in this study involved genetically engineered mice predisposed to osteoarthritis development, allowing precise manipulation of mitochondrial cholesterol content. By employing pharmacological agents and genetic knockdown approaches to attenuate mitochondrial cholesterol accumulation, the investigators successfully reduced joint inflammation and cartilage erosion. This experimental strategy provided compelling evidence that mitochondria serve as critical intermediaries linking cholesterol metabolism to osteoarthritis progression.”