BMPs and the muscle–bone connection Roberta Sartori a,b, ⁎, Marco Sandri a,b,c, ⁎ a Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy b Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy c Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy abstract article info Article history: Received 8 December 2014 Revised 8 May 2015 Accepted 20 May 2015 Available online 31 May 2015 Edited by: Michaela Kneissel, David Glass and Kavitha Narayanasamy Keywords: Skeletal muscle BMP Myostatin Muscle wasting Hypertrophy Muscle and bone are two intimately connected tissues. A coordinated interplay between these tissues at mechan- ical levels is required for their development, function and ageing. Evidence is emerging that several genes and molecular pathways exert a pleiotropic effect on both muscle and bone. Bone morphogenetic proteins (BMPs) are secreted signal factors belonging to the transforming growth factor β (TGFβ) superfamily. BMPs have an es- sential role during bone and cartilage formation and maintenance. Recently, we and others have demonstrated that the BMP pathway also has a role in controlling adult skeletal muscle mass. Thus, BMPs become crucial reg- ulators of both bone and muscle formation and homeostasis. In this review we will discuss the signalling down- stream BMP and its role in muscle–bone interaction. This article is part of a Special Issue entitled “Muscle Bone Interactions”. © 2015 Published by Elsevier Inc. Contents Bone and muscle interconnection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Muscle–bone cross-talk and soluble factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 The transforming growth factor beta (TGFβ) superfamily and downstream signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 BMPs and the regulation of skeletal muscle mass. Role during myogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 BMPs and regulation of adult muscle mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Bone and muscle interconnection Bone and muscle are two of the most intimately and mechanically connected tissues in the body. In addiction, they are endocrine organs that secrete factors that can influence others organs and tissues [1–3]. It is reasonable to speculate that their connection is based also on recip- rocal signalling cross-talk. Even if this aspect needs to be investigated more deeply in the future, there are several lines of evidence that bone and muscle, originated by the same mesenchymal precursor [4, 5], share genetic determinants and develop, function, and age as a whole [6]. During embryogenesis the musculoskeletal unit (bone–tendon– muscle) undergoes development in a very synchronized and spatially regulated way. For example, muscle contraction is important for bone [7] and joint development [8], as shown by the altered joint formation induced in the chick embryo in ovo by neuromuscular blocking agents. Muscle–tendon junction is the site where contractile force produced by muscle fibers is transmitted from myofilaments to tendon fibers. The position of both myogenic and scleraxis (a transcription factor con- sidered a marker of tendon cells) positive cells is determined by bone morphogenetic protein (BMP) signal and is reciprocally influenced dur- ing foetal development [9]. Tendon development requires the presence of muscle [10] and vice versa [11]. In developing chick limb, a subpopu- lation of Pax7+ and BMP-responsive cells has been identified at the extremities of growing muscles in close proximity to tendons that pro- duce BMP4. This paracrine signal regulates the correct number of foetal Bone 80 (2015) 37–42 ⁎ Corresponding authors. E-mail addresses: roberta_sartori@hotmail.com (R. Sartori), marco.sandri@unipd.it (M. Sandri). http://dx.doi.org/10.1016/j.bone.2015.05.023 8756-3282/© 2015 Published by Elsevier Inc. Contents lists available at ScienceDirect Bone journal homepage: www.elsevier.com/locate/bone