Abstract
Skeletal muscle and bone are highly interrelated, and previous proteomic analyses suggest that lumican is one of muscle-derived factors. To further understand the role of lumican as a myokine affecting adjacent bone metabolism, we investigated the effects of lumican on osteoblast biology. Lumican expression was significantly higher in the cell lysates and conditioned media (CM) of myotubes than those of undifferentiated myoblasts, and the known anabolic effects of myotube CM on osteoblasts were reduced by excluding lumican from the CM. Lumican stimulated preosteoblast viability and differentiation, resulting in increased calvaria bone formation. The expression of osteoblast differentiation markers was consistently increased by lumican. Lumican increased the phosphorylation of ERK, whereas ERK inhibitors completely reversed lumican-mediated stimulation of Runx2 and ALP activities in osteoblasts. Results of a binding ELISA experiment in osteoblasts show that transmembrane integrin α2β1 directly interacted with lumican, and an integrin α2β1 inhibitor attenuated the stimulation of ERK and ALP activities by lumican. Taken together, the results indicate that muscle-derived lumican stimulates bone formation via integrin α2β1 and the downstream ERK signal, indicating that this is a potential therapeutic target for metabolic bone diseases.
Highlights
Bone and skeletal muscle contribute the largest amount of tissues in a lean individual; both respond to physical activity and play a role in protecting internal organs (Tagliaferri et al, 2015)
To determine whether lumican acts as a myokine that affects bone metabolism, C2C12 myoblasts infected with lumican short hairpin RNA (shRNA) conditioned media (CM) were differentiated into myotubes in the presence of 2% horse serum (Figure 1D), and their CM was collected
The stimulation of preosteoblast viability by myotube CM was markedly diminished by lumican silencing, and the addition of lumican to these CM rescued the reduced preosteoblast viability resulting from lumican knockdown (Figure 1E)
Summary
Bone and skeletal muscle contribute the largest amount of tissues in a lean individual; both respond to physical activity and play a role in protecting internal organs (Tagliaferri et al, 2015). Accumulating clinical evidence indicates that bone and muscle health are highly interrelated, working together throughout an individual’s lifetime (Hirschfeld et al, 2017; Bettis et al, 2018). Concomitant losses in bone and muscle mass are frequently observed in older adults (Verschueren et al, 2013; Kim et al, 2015). Both osteoporosis and sarcopenia contribute to the development of fragility fractures that contribute to high disability and mortality (Yu et al, 2014). Effective measures to prevent fractures require continuous efforts to understand the mechanisms underlying bone-muscle crosstalk. The parallel changes of bone and muscle have been explained by the mechanical force transduction generated by muscle contraction to the adjacent bone
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