While data supports a role for activins as both positive and nega

While data supports a role for activins as both positive and negative regulators of bone, the role of BMP3 as a negative regulator of bone is better documented. Osteoblasts PI3K activation and osteocytes secrete BMP3 and targeted deletion of BMP3 results in increased bone mass [36] and [37]. Further analyses revealed that BMSCs isolated from BMP3 null mice showed an increase in colony number, size and ability to differentiate into osteoblasts [36]. Interestingly, transgenic overexpression of BMP3 in mice leads to delayed osteogenesis and spontaneous rib fractures [38]. Additional in vitro

experiments demonstrated that BMP3 can antagonize both BMP2 and BMP4 through an ActRIIB dependent mechanism [36]. The data strongly supports BMP3 as a negative regulator of bone health. This study evaluated the role of myostatin in regulating bone mass in young adult mice using two distinct pharmacologic inhibitors, a neutralizing antibody to myostatin and a soluble Afatinib ic50 myostatin decoy receptor (ActRIIB-Fc). In addition,

studies were performed in both Mstn−/− and Bmp3−/− mice to begin to define the therapeutic mechanism of action of ActRIIB-Fc. The results of these studies indicate that ActRIIB-Fc modulates bone mass primarily through myostatin and BMP3-independent mechanisms. Female C57BLJ/6 mice were purchased from Charles River Laboratory and group housed (Charles River Laboratory, Andover MA). Myostatin (Mstn) and BMP3 knockout colonies were housed and managed by Taconic (Taconic, Germantown NY, USA). All animals were maintained in a facility with a 12 h light–dark cycle and fed standard mouse pelleted food (PMI Feeds Chow #5001 PharmaServ, Framingham, MA) and water ad libitum. All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) and were carried out under the Association for Assessment and Accreditation of Laboratory Animal guidelines. 8 week old female C57BLJ/6, Mstn−/− or Bmp3−/− mice were administered either Myosin weekly intraperitoneal injections (i.p.) of

vehicle (Veh) (PBS or Tris–sucrose, n = 8), a neutralizing antibody to myostatin (60 mg/kg JA16, Pfizer, Cambridge MA, n = 8) or a soluble myostatin decoy receptor (10 mg/kg ActRIIB-Fc, Pfizer, Cambridge, MA, n = 8) for a period of 4 weeks. The neutralizing antibody has previously been shown to inhibit GDF-8 and -11 but not other members of the TGFβ family such as activin A, while the decoy receptor was shown to inhibit many members of the TGFβ family including GDF-8, -11 and activins A, B and AB [28] and [39]. Comparing the effects of both molecules on muscle and bone mass allowed the authors to determine the specific contribution of myostatin inhibition to these studies. The doses were chosen based on previous experiments with these molecules and reflect optimal doses to observe increased muscle mass. The construction, expression and purification of ActRIIB-Fc were previously described [32].

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