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Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.

Bone morphogenetic proteins (BMPs) are crucial growth factors from embryonic development up to adult organ/tissue homeostasis since they regulate versatile processes such as stem cell maintenance, differentiation and migration. Aberrant signalling leads to pathologies including cancer or musculoskeletal and vascular diseases. Here, we provide an overview of the BMP signalling cascade and its complex regulation and show how we investigate this tightly controlled protein network in physiological and pathological model systems.

Insulin-resistance is the main cause of type 2 diabetes. Here we describe the identification and characterization of BMP2 and BMP6 as new insulin-sensitizing growth factors in mature adipocytes. We show that BMP2 and BMP6 lead to enhanced insulin-mediated glucose uptake in both insulin-sensitive and -insensitive adipocytes. We exclude a direct effect of BMP2 or BMP6 on translocation of GLUT4 to the plasma membrane and demonstrate that these BMPs increase GLUT4 protein levels equipotent to Rosiglitazone. BMPs induce expression of PPARγ as the crucial mediator for the insulin-sensitizing effect. A comprehensive RNA-Seq analysis in mature adipocytes revealed regulation of both BMP/Smad and PPARγ target genes. The effects of BMP2 and BMP6 are not completely redundant and include regulation of genes involved in glucose and fatty acid metabolism and adipokine expression. Collectively, these findings suggest the BMP2 and BMP6 pathway(s) as promising new drug targets to treat insulin resistance.

The musculoskeletal system is a tight network of many tissues. Coordinated interplay at a biochemical level between tissues is essential for development and repair. Traumatic injury usually affects several tissues and represents a large challenge in clinical settings. The current demand for potent growth factors in such applications thus accompanies the keen interest in molecular mechanisms and orchestration of tissue formation. Of special interest are multitasking growth factors that act as signals in a variety of cell types, both in a paracrine and in an autocrine manner, thereby inducing cell differentiation and coordinating not only tissue assembly at specific sites but also maturation and homeostasis. We concentrate here on bone morphogenetic proteins (BMPs), which are important crosstalk mediators known for their irreplaceable roles in vertebrate development. The molecular crosstalk during embryonic musculoskeletal tissue formation is recapitulated in adult repair. BMPs act at different levels from the initiation to maturation of newly formed tissue. Interestingly, this is influenced by the spatiotemporal expression of different BMPs, their receptors and co-factors at the site of repair. Thus, the regenerative potential of BMPs needs to be evaluated in the context of highly connected tissues such as muscle and bone and might indeed be different in more poorly connected tissues such as cartilage. This highlights the need for an understanding of BMP signaling across tissues in order to eventually improve BMP regenerative potential in clinical applications. In this review, the distinct members of the BMP family and their individual contribution to musculoskeletal tissue repair are summarized by focusing on their paracrine and autocrine functions.

Bone morphogenetic proteins (BMPs) are members of the TGFβ growth factor superfamily and have important roles in proliferation, development, differentiation of embryonic and adult cells, as well as in tissue regeneration. BMPs signal via two transmembrane serine/threonine kinase receptors, the BMP type I (BMPRIa and BMPRIb) and BMP type II (BMPRII) receptors which can form homo- and heterooligomeric complexes. They occur in distinct membrane areas, are differently modulated upon ligand binding and are subsequently endocytosed [1]. Upon ligand binding to the receptor complex a signaling cascade via Smad proteins or independent of Smads is initiated and results in expression of specific target genes. cGMP-dependent kinase I (cGKI) was identified as a BMPRII interacting protein in a proteomics-based approach using the cytoplasmic BMPRII-tail region as bait [2]. cGKI is a cytoplasmic serine/threonine kinase and signals via the NO/cGMP/cGK pathway and is involved in regulation of growth, differentiation and apoptosis of cells [3]. The involvement of cGKI in BMP signaling could be validated as it positively influences receptor and Smad activation at the plasma membrane as well as it enhances the transcription of target genes in the nucleus [4]. New results hint towards the fact that cGKI is involved in endocytotic events in BMP signaling, as it dynamically interacts with BMPRII upon BMP-2 stimulation and enhances the internalization of the receptor. Interfering with endocytosis in the cell inhibits BMP signaling mediated by BMP-2 and cGKI. Clinical evidence for the involvement of cGKI in BMP-signaling is given by the fact that mutations in the BMPRII are related to the development of primary arterial hypertension (PAH) [5]. Patients with PAH suffer from vasoconstriction and elevated pressure in the pulmonary arteries, but the distinct pathway leading to the specific phenotype is still unraveled. We could show that ineffective signaling caused by mutant BMPRII found in PAH could be compensated through cGKI [4].