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J. Biol. Chem., Vol. 280, Issue 45, 37782-37789, November 11, 2005

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Pregnancy-associated Plasma Protein-A Regulates Myoblast Proliferation and Differentiation through an Insulin-like Growth Factor-dependent Mechanism^*

Ashok Kumar, Subburaman Mohan¶||, Jacqueline Newton, Mark Rehage, Kiet Tran, David J. Baylink¶, and Xuezhong Qin1

From the Musculoskeletal Disease Center, J. L. Pettis Memorial Veterans Affairs Medical Center and Departments of Medicine, ^¶Biochemistry, and ^||Physiology, Loma Linda University, Loma Linda, California 92357

Pregnancy-associated plasma protein-A (PAPP-A), a member of the metalloproteinase superfamily, is an important regulator of mammalian growth and development. However, the role of PAPP-A and its mechanism of action in various cellular processes remain unknown. In this study, we have investigated the role of PAPP-A in skeletal myogenesis using C2C12 myoblasts. Recombinant PAPP-A was purified from the conditioned medium of HT1080 cells overexpressing PAPP-A. Treatment of C2C12 myoblasts with PAPP-A increased their proliferation in a dose- and time-dependent manner. Addition of exogenous PAPP-A also increased the myotube formation and the activity of creatine kinase in C2C12 cultures. Transient overexpression of the full-length PAPP-A-(1-1547), but not truncated protease-inactive N-terminal PAPP-A-(1-920) or C-terminal PAPP-A-(1100-1547), significantly enhanced the proliferation of C2C12 myoblasts. In vitro and in situ experiments demonstrated that PAPP-A cleaves insulin-like growth factor-binding protein (IGFBP)-2, but not IGFBP-3, in the conditioned medium of C2C12 myoblasts. Overexpression of PAPP-A led to degradation of the IGFBP-2 produced by C2C12 myoblasts and increased free IGF-I concentrations without affecting total IGF-I concentrations. Addition of protease-resistant IGFBP-4 completely abolished the PAPP-A-induced proliferation of C2C12 myoblasts. Our results demonstrate that 1) PAPP-A increases the proliferation and differentiation of myoblasts, 2) the stimulatory effect of PAPP-A on myogenesis is governed by its proteolytic activity, and 3) PAPP-A promotes skeletal myogenesis by increasing the amount of free IGFs via specific degradation of IGFBP-2 produced by myoblasts.

Received for publication, May 13, 2005 , and in revised form, July 29, 2005.

^* This work was supported by a Department of Veterans Affairs grant (Merit Review to X. Q.), National Institutes of Health Grants R01 AR45210 (to X. Q.) and R01 AR31062 (to S. M.), and grants from the Muscular Dystrophy Association (to A. K.) and Loma Linda University (to X. Q.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Musculoskeletal Disease Center, J. L. Pettis Veterans Affairs Medical Center (151), 11201 Benton St., Loma Linda, CA 92357. Tel.: 909-825-7084 (ext. 2773); Fax: 909-796-1680; E-mail: Xuezhong.Qin{at}med.va.gov.

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