Osteoactivin upregulates expression of MMP-3 and MMP-9 in fibroblasts infiltrated into denervated skeletal muscle in mice.
In this study, we examined pathophysiological roles of osteoactivin, a functionally unknown type I membrane glycoprotein, in mouse skeletal muscle atrophied by denervation (sciatic neurectomy). Denervation increased the amounts of osteoactivin, vimentin, matrix metalloproteinase-3 (MMP-3), and MMP-9 in mouse gastrocnemius muscle. Interestingly, immunohistochemical analysis revealed that vimentin, MMP-3, and MMP-9 were mainly present in fibroblast-like cells infiltrated into denervated mouse gastrocnemius muscle, whereas osteoactivin was expressed in the sarcolemma of myofibers adjacent to the fibroblast-like cells. On the basis of these findings, we reasoned that osteoactivin in myocytes was involved in activation of the infiltrated fibroblasts. To address this issue, we examined effects of osteoactivin on expression of MMPs in fibroblasts in vitro and in vivo. Overexpression of osteoactivin in NIH-3T3 fibroblasts induced expression of MMP-3, but not in mouse C(2)C(12) myoblasts, indicating that osteoactivin might functionally target fibroblasts. Treatment with recombinant mouse osteoactivin increased the amounts of collagen type I, MMP-3, and MMP-9 in mouse NIH-3T3 fibroblasts. The upregulated expression of these fibroblast marker proteins was significantly inhibited by heparin, but not by an integrin inhibitor, indicating that a heparin-binding motif in the extracellular domain might be an active site of osteoactivin. In osteoactivin-transgenic mice, denervation further enhanced expression of MMP-3 and MMP-9 in fibroblasts infiltrated into gastrocnemius muscle, compared with wild-type mice. Our present results suggest that osteoactivin might function as an activator for fibroblasts infiltrated into denervated skeletal muscles and play an important role in regulating degeneration/regeneration of extracellular matrix.
Ogawa
Takayuki
T
Dept. of Orthopaedics, The University of Tokushima School of Medicine, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Nikawa
Takeshi
T
Furochi
Harumi
H
Kosyoji
Miki
M
Hirasaka
Katsuya
K
Suzue
Naoto
N
Sairyo
Koichi
K
Nakano
Shunji
S
Yamaoka
Takashi
T
Itakura
Mitsuo
M
Kishi
Kyoichi
K
Yasui
Natsuo
N
D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology; D015870:Gene Expression / Q000502:physiology; D006614:Hindlimb; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology / Q000502:physiology*; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects; D041681:NIH 3T3 Cells; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012038:Regeneration / Q000502:physiology; D012583:Schwann Cells / Q000166:cytology / Q000201:enzymology; D015854:Up-Regulation
D024042:Collagen Type I; D008562:Membrane Glycoproteins; D010982:Platelet-Derived Growth Factor; D016222:Fibroblast Growth Factor 2; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9