Melatonin attenuates inflammatory bone loss by alleviating mitophagy and lactate production

Mitochondrial homeostasis plays a major role in the progression of chronic inflammatory bone loss which has a complex pathogenesis with unsatisfactory therapeutic efficiency. Recently, melatonin has been shown to recipient mitochondrial function and bone formation. However, the effects and underlying molecular mechanism of melatonin in chronic inflammatory bone loss remain unclear. Here, we reported that melatonin ameliorated lipopolysaccharide (LPS)-induced inflammatory bone loss by improving osteogenesis. We found that melatonin rescued LPS-induced mitochondrial dysfunction and metabolic reprogramming in osteoblasts, resulting in reduced osteogenesis impairment. Mechanistically, melatonin inhibited mitochondrial reactive oxygen species (mtROS) production by suppressing LPS-induced mitophagy, which attenuated the activation of the mtROS/HIF-1α/pyruvate dehydrogenase kinase 1 (PDK1) axis. Moreover, melatonin restored pyruvate dehydrogenase (PDH) activity by inhibiting phosphorylation of PDH through the mtROS/HIF-1α/PDK1 axis and eventually downregulated lactate production. These findings indicate the therapeutic effects of melatonin against chronic inflammatory bone loss and demonstrated a potential treatment strategy against inflammatory osteogenic disorders through regulating mitochondrial dysfunction and metabolic reprogramming.

Graphical abstract

The present study reports that melatonin ameliorates LPS-induced bone loss by improving mitochondrial function in osteoblasts and demonstrates that melatonin inhibits LPS-induced mitophagy, which, in turn, suppressing the mtROS/HIF-1α/PDK1 axis, resulting in reduced lactate production and eventually promoting osteogenesis.