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There is a complex interaction between HIF-1 and HIF-2 depending on degree and duration of hypoxia, including non-coding RNA (microRNA) which also includes a third HIF (HIF-3), this interaction is called the HIF-shift [78]

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Beyond simple biomechanics, where each 1 kg of weight gain multiplies knee joint load by 34 kg, accelerating cartilage wear and activating pathogenic pathways like Wnt/ -catenin, the endocrine function of fat is paramount (14, 15)