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CCN2 acts as an anabolic growth factor to regulate osteoblast differentiation and function. CCN2 is induced by TGF-β1 and acts as a mediator of TGF-β1 induced matrix production in osteoblasts and Src is required for CCN2 induction by TGF-β1; however, the molecular mechanisms that control CCN2 induction in osteoblasts are poorly understood. AFAP1 binds activated forms of Src and can direct the activation of Src in certain cell types, however a role for AFAP1 downstream of TGF-β1 or in osteoblats is undefined. In this study, we investigated the role of AFAP1 for CCN2 induction by TGF-β1 in primary osteoblasts. We demonstrated that AFAP1 expression in osteoblasts occurs in a biphasic pattern with maximal expression levels occurring during osteoblast proliferation (~day 3), reduced expression during matrix production/maturation (~day 14-21), an a further increase in expression during mineralization (~day 21). AFAP1 expression is induced by TGF-β1 treatment in osteoblasts during days 7, 14 and 21. In osteoblasts, AFAP1 binds to Src and is required for Src activation by TGF-β1 and CCN2 promoter activity and protein induction by TGF-β1 treatment was impaired using AFAP1 siRNA, indicating the requirement of AFAP1 for CCN2 induction by TGF-β1. We also demonstrated that TGF-β1 induction of extracellular matrix protein collagen XIIa occurs in an AFAP1 dependent fashion. This study demonstrates that AFAP1 is an essential downstream signaling component of TGF-β1 for Src activation, CCN2 induction and collagen XIIa in osteoblasts.

Selective estrogen receptor modulators (SERMs) are a diverse group of nonsteroidal compounds that function as agonists or antagonists for estrogen receptors (ERs) in a target gene-specific and tissue-specific fashion. SERM specificity involves tissue-specific expression of ER subtypes, differential expression of co-regulatory proteins in various tissues, and varying ER conformational changes induced by ligand binding. To date, the major clinical applications of SERMs are their use in the prevention and treatment of breast cancer, the prevention of osteoporosis, and the maintenance of beneficial serum lipid profiles in postmenopausal women. However, SERMs have also been found to promote adverse effects, including thromboembolic events and, in some cases, carcinogenesis, that have proven to be obstacles in their clinical utility. In this review, we discuss the mechanisms of SERM tissue specificity and highlight the therapeutic application of well-known and emergent SERMs.

CCN2 acts as an anabolic growth factor to regulate osteoblast differentiation and function. CCN2 is induced by TGF-[beta]1 and acts as a mediator of TGF-[beta]1 induced matrix production in osteoblasts and Src is required for CCN2 induction by TGF-[beta]1; however, the molecular mechanisms that control CCN2 induction in osteoblasts are poorly understood. AFAP1 binds activated forms of Src and can direct the activation of Src in certain cell types, however a role for AFAP1 downstream of TGF-[beta]1 or in osteoblats is undefined. In this study, we investigated the role of AFAP1 for CCN2 induction by TGF-[beta]1 in primary osteoblasts. We demonstrated that AFAP1 expression in osteoblasts occurs in a biphasic pattern with maximal expression levels occurring during osteoblast proliferation (~day 3), reduced expression during matrix production/maturation (~day 14-21), an a further increase in expression during mineralization (~day 21). AFAP1 expression is induced by TGF-[beta]1 treatment in osteoblasts during days 7, 14 and 21. In osteoblasts, AFAP1 binds to Src and is required for Src activation by TGF-[beta]1 and CCN2 promoter activity and protein induction by TGF-[beta]1 treatment was impaired using AFAP1 siRNA, indicating the requirement of AFAP1 for CCN2 induction by TGF-[beta]1. We also demonstrated that TGF-[beta]1 induction of extracellular matrix protein collagen XIIa occurs in an AFAP1 dependent fashion. This study demonstrates that AFAP1 is an essential downstream signaling component of TGF-[beta]1 for Src activation, CCN2 induction and collagen XIIa in osteoblasts.

Background CCN2 acts as an anabolic growth factor to regulate osteoblast differentiation and function. CCN2 is induced by TGF-[Beta]1 and acts as a mediator of TGF-[Beta]1 induced matrix production in osteoblasts and Src is required for CCN2 induction by TGF-[Beta]1; however, the molecular mechanisms that control CCN2 induction in osteoblasts are poorly understood. AFAP1 binds activated forms of Src and can direct the activation of Src in certain cell types, however a role for AFAP1 downstream of TGF-[Beta]1 or in osteoblats is undefined. In this study, we investigated the role of AFAP1 for CCN2 induction by TGF-[Beta]1 in primary osteoblasts. Results We demonstrated that AFAP1 expression in osteoblasts occurs in a biphasic pattern with maximal expression levels occurring during osteoblast proliferation (~day 3), reduced expression during matrix production/maturation (~day 14-21), an a further increase in expression during mineralization (~day 21). AFAP1 expression is induced by TGF-[Beta]1 treatment in osteoblasts during days 7, 14 and 21. In osteoblasts, AFAP1 binds to Src and is required for Src activation by TGF-[Beta]1 and CCN2 promoter activity and protein induction by TGF-[Beta]1 treatment was impaired using AFAP1 siRNA, indicating the requirement of AFAP1 for CCN2 induction by TGF-[Beta]1. We also demonstrated that TGF-[Beta]1 induction of extracellular matrix protein collagen XIIa occurs in an AFAP1 dependent fashion. Conclusions This study demonstrates that AFAP1 is an essential downstream signaling component of TGF-[Beta]1 for Src activation, CCN2 induction and collagen XIIa in osteoblasts.