Muscle-Derived Lumican Stimulates Bone Formation via Integrin α2β1 and the Downstream ERK Signal

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 musclederived lumican stimulates bone formation via integrin α2β1 and the downstream ERK signal, indicating that this is a potential therapeutic target for metabolic bone diseases.

TGFβ1 Improves the Proliferation of Decellularized and Aligned Skeletal Muscle in Extracellular Matrix Hydrogels by m6A Modification-Mediated Integrin Through Inducing ERK Phosphorylation

“…Integrin activates FAK/paxillin/AKT signaling pathway and affects the expression of the proliferative marker Ki67 in tumors [44]. Recent studies have shown that transmembrane integrin α2β1 directly interacts with lumican, and activates ERK and ALP activities in osteoblasts [45]. Our study rst indicated that METTL3 regulates integrin and attenuates its m 6 A-mediated degradation.…”

Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

“…Accordingly, many researchers have sought to develop anti-osteoporotic drugs that can dissociate bone resorption from bone formation. Recent work showed that lumican exerts anabolic effects on bones by stimulating osteoblastogenesis [ 14 ]. Furthermore, this study revealed that lumican directly suppresses in vitro bone resorption as well as osteoclastogenesis.…”

“…As a candidate receptor of lumican in osteoclasts, we focused on transmembrane integrin α2β1, which is involved in the activities of lumican in several cell types [ 26 , 27 ]. Recent work demonstrated that integrin α2β1 mediates the beneficial effects of lumican in osteoblasts [ 14 ]. Integrin αVβ3 was also regarded as a potential target because this is the most abundant form of integrins in osteoclasts [ 28 ].…”

“…Although lumican belongs to the SLRP family and may therefore be involved in bone metabolism [ 5 ], the effects of lumican on bone biology are not yet fully understood. In vitro and animal experiments have demonstrated that lumican promotes preosteoblast viability and differentiation via integrin α2β1 and downstream ERK signaling, leading to bone formation [ 14 ]. To further elucidate the role of lumican in bone metabolism, we investigated its effects on osteoclasts and found that it inhibits osteoclastogenesis and bone resorption by suppressing Akt signaling.…”

Effect of CCL11 on In Vitro Myogenesis and Its Clinical Relevance for Sarcopenia in Older Adults

“…The protein concentration was measured with a bicinchoninic Acid (BCA) protein assay kit (Pierce Chemical Co., Rockford, IL, USA). Protein samples were separated by SDS-polyacrylamide gel electrophoresis (PAGE), transferred to a polyvinylidene fluoride membrane, and immunoblotted with antibodies [25]. The primary antibodies were: MyHC (MF20); myogenin (sc-12732) and CCR5 (sc-178933) (Santa Cruz Biotechnology, Dallas, TX, USA); and β-tubulin (T2200; Sigma-Aldrich).…”