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Key Points Phylogenetic analysis indicates that the bone morphogenetic protein (BMP) pathway is ancient and highly conserved across the animal kingdom Gene duplication and divergence has created a diverse matrix of BMP ligand–receptor pairs that achieve sophisticated control of signalling through variable activity profiles and functional redundancy Members of the BMP superfamily affect almost all aspects of bone, cartilage and joint biology Altered BMP signalling is a major underlying cause of human skeletal disorders Modulation of BMP signalling is emerging as a promising therapeutic strategy for improving bone mass and bone quality, ameliorating diseases of skeletal overgrowth and repairing damage to bones and joints Bone morphogenetic proteins (BMPs) have been implicated in almost all aspects of bone, cartilage and joint biology. Here, Valerie Salazar and colleagues discuss BMP superfamily signalling in the context of skeletal development and joint morphogenesis, and summarize the status of the BMP pathway as a therapeutic target for treating skeletal trauma and disease. Since the identification in 1988 of bone morphogenetic protein 2 (BMP2) as a potent inducer of bone and cartilage formation, BMP superfamily signalling has become one of the most heavily investigated topics in vertebrate skeletal biology. Whereas a large part of this research has focused on the roles of BMP2, BMP4 and BMP7 in the formation and repair of endochondral bone, a large number of BMP superfamily molecules have now been implicated in almost all aspects of bone, cartilage and joint biology. As modulating BMP signalling is currently a major therapeutic target, our rapidly expanding knowledge of how BMP superfamily signalling affects most tissue types of the skeletal system creates enormous potential to translate basic research findings into successful clinical therapies that improve bone mass or quality, ameliorate diseases of skeletal overgrowth, and repair damage to bone and joints. This Review examines the genetic evidence implicating BMP superfamily signalling in vertebrate bone and joint development, discusses a selection of human skeletal disorders associated with altered BMP signalling and summarizes the status of modulating the BMP pathway as a therapeutic target for skeletal trauma and disease.

Much of the mammalian skeleton originates from a cartilage template eventually replaced by bone via endochondral ossification. Despite much knowledge about growth factors and nuclear proteins in skeletal development, little is understood about the role of metabolic regulation. Here we report that genetic deletion of the glucose transporter Glut1 (Slc2a1), either before or after the onset of chondrogenesis in the limb, severely impairs chondrocyte proliferation and hypertrophy, resulting in dramatic shortening of the limbs. The cartilage defects are reminiscent to those caused by deficiency in Bmp signaling. Importantly, deletion of Bmpr1a in chondrocytes markedly reduces Glut1 levels in vivo, whereas recombinant BMP2 increases Glut1 mRNA and protein levels, boosting glucose metabolism in primary chondrocytes. Biochemical studies identify a Bmp-mTORC1-Hif1a signaling cascade resulting in upregulation of Glut1 in chondrocytes. The results therefore uncover a hitherto unknown connection between Bmp signaling and glucose metabolism in the regulation of cartilage development. It is unclear how metabolic regulation affects development of the skeleton. Here, the authors show that deletion of the glucose transporter Glut1 ( Slc2a1 ) both prior to and following chondrogenesis in the mouse limb impairs chondrocyte proliferation and shortening of the limbs, modulated by BMP signaling.

BMP2, BMP4 and BMP16 form a subfamily of bone morphogenetic proteins acting as pleiotropic growth factors during development and as bone inducers during osteogenesis. BMP16 is the most recent member of this subfamily and basic data regarding protein structure and function, and spatio-temporal gene expression is still scarce. In this work, insights on BMP16 were provided through the comparative analysis of structural and functional data for zebrafish BMP2a, BMP2b, BMP4 and BMP16 genes and proteins, determined from three-dimensional models, patterns of gene expression during development and in adult tissues, regulation by retinoic acid and capacity to activate BMP-signaling pathway. Structures of Bmp2a, Bmp2b, Bmp4 and Bmp16 were found to be remarkably similar; with residues involved in receptor binding being highly conserved. All proteins could activate the BMP-signaling pathway, suggesting that they share a common function. On the contrary, stage-and tissue-specific expression of bmp2, bmp4 and bmp16 suggested the genes might be differentially regulated (e.g. different transcription factors, enhancers and/or regulatory modules) but also that they are involved in distinct physiological processes, although with the same function. Retinoic acid, a morphogen known to interact with BMP-signaling during bone formation, was shown to downregulate the expression of bmp2, bmp4 and bmp16, although to different extents. Taxonomic and phylogenetic analyses indicated that bmp16 diverged before bmp2 and bmp4, is not restricted to teleost fish lineage as previously reported, and that it probably arose from a whole genomic duplication event that occurred early in vertebrate evolution and disappeared in various tetrapod lineages through independent events.

Despite the high prevalence of ischemic heart diseases worldwide, no antibody-based treatment currently exists. Starting from the evidence that a specific isoform of the Bone Morphogenetic Protein 1 (BMP1.3) is particularly elevated in both patients and animal models of myocardial infarction, here we assess whether its inhibition by a specific monoclonal antibody reduces cardiac fibrosis. We find that this treatment reduces collagen deposition and cross-linking, paralleled by enhanced cardiomyocyte survival, both in vivo and in primary cultures of cardiac cells. Mechanistically, we show that the anti-BMP1.3 monoclonal antibody inhibits Transforming Growth Factor β pathway, thus reducing myofibroblast activation and inducing cardioprotection through BMP5. Collectively, these data support the therapeutic use of anti-BMP1.3 antibodies to prevent cardiomyocyte apoptosis, reduce collagen deposition and preserve cardiac function after ischemia. Here the authors show that a monoclonal antibody against a soluble isoform of Bone Morphogenetic Protein 1 prevents cardiac cell death, reducing fibrosis and preserving cardiac function after myocardial ischemia.

Animal studies have demonstrated the therapeutic effect of mesenchymal stem cells (MSCs) on osteogenesis, but little is known about the functions of exosomes (Exos) released by bone MSCs (BMSCs). Here, we investigated the effect of BMSC Exos on steroid-induced femoral head necrosis (SFHN) and explored the vital genes involved in this process. BMSCs were isolated from healthy and SFHN rats. BMSC Exos were isolated using the Exosome Precipitation Kit and characterized by transmission electron microscopy and Western blotting. SFHN BMSCs were incubated with Exos from healthy BMSCs. Osteogenic ability was assessed by oil red O staining and alizarine red staining. Differentially expressed genes (DEGs) induced by Exos were screened using the Osteogenesis RT2 Profiler PCR Array. The effect of upregulated was examined using lentivirus-mediated siRNA. The results revealed that BMSC Exos were 100-150 nm in size and expressed CD63. Moreover, BMSC Exo-treated SFHN cells exhibited suppressed adipogenesis compared to model cells. PCR array showed that eleven and nine genes were upregulated and downregulated, respectively, in the BMSC Exo-treated SFHN cells compared to the model group. Among the DEGs, osteogenesis-related genes, including , , , , and , may play important roles in SFHN. Furthermore, the DEGs were mainly involved in immune response, osteoblast differentiation, and in the transforming growth factor-β/bone morphogenetic protein signaling pathway. The level of the SOX9 protein was upregulated by Exos, and silencing significantly decreased the osteogenic effect of BMSC Exos. Our data suggest that Exos derived from BMSCs mainly affect SFHN osteogenesis, and this finding can be further investigated to develop a novel therapeutic agent for SFHN.

Bone morphogenetic proteins (BMPs) are secreted growth factors that belong to the transforming growth factor beta superfamily. BMPs have been implicated in physiological processes, but they are also involved in many pathological conditions. Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS); however, its etiology remains elusive. Some evidence points to BMPs as important players in the pathogenesis of inflammatory and autoimmune disorders. In the present work, we studied the expression of BMP2, BMP4, BMP5, BMP6, BMP7, BMP type II receptor, and noggin in the immune system during different phases of experimental autoimmune encephalomyelitis (EAE). Major changes in the expression of BMPs took place in the initial phases of EAE. Indeed, those changes mainly affected BMP6 (whose expression was abrogated), BMP2, and BMP7 (whose expression was increased). In addition, we showed that in vivo inhibition of the BMP signaling pathway with small molecules ameliorated the already established clinical symptoms of EAE, as well as the CNS histopathological features. At the immune level, we observed an expansion of plasmacytoid dendritic cells (pDCs) in mice treated with small molecules that inhibit the BMP signaling pathway. pDCs could play an important role in promoting the expansion of antigen-specific regulatory T cells. Altogether, our data suggest a role for BMPs in early immune events that take place in myelin oligodendrocyte glycoprotein (MOG)-induced EAE. In addition, the clinical outcome of the disease was improved when the BMP signaling pathway was inhibited in mice that presented established EAE symptoms.

This study investigated the differential gene expression of BMPs in chick retinal pigment epithelium (RPE) during recovery from short term exposure to optical defocus and form-deprivation (FD) treatments. 14-day old White-Leghorn chicks wore either monocular +10 or -10 D lenses, or diffusers for 2 or 48 h, after which eyes were allowed unobstructed vision for up to 96 h. Over this recovery period, refractive errors and choroidal thickness (ChT) were tracked using retinoscopy and high-frequency A-scan ultrasonography. Real-time PCR was used to examine the expression of BMP2, 4, and 7 genes in RPE samples collected 0, 15 min, 2, 24, 48, and 96 h after the termination of treatments. Expression levels in treated eyes and their contralateral control eyes were compared. After the termination of the lens and diffuser treatments, eyes gradually recovered from induced shifts in refractive error. With all three treatments, ChT changes reached statistical significance after 48 h of treatment, be it thinning with the -10 D lens and diffuser treatments (-0.06 ± 0.03mm, p < 0.05; -0.11 ± 0.04 mm, p < 0.05, resp.), or thickening with the +10 D lens (0.31 ± 0.04 mm, p < 0.001). BMP2 gene expression was rapidly upregulated in eyes wearing the +10 D lens, being statistical significance after 2 h, as well as 48 h of treatment. With the 2 h treatment, the latter gene expression pattern persisted for 15 min into the recovery period, before decreasing to the same level as that of contralateral control eyes, with a short-lived rebound, i.e., upregulation, 24 h into the recovery period. With the longer, 48 h treatment, BMP2 gene expression decreased more gradually, from 739 ± 121% at the end of the treatment period, to 72 ± 14% after 48 h of recovery. Two and 48 h of both -10 D and FD treatments resulted in BMP2 gene expression downregulation, with the time taken for gene expression levels to fully recover varying with the duration of initial treatments. In both cases, BMP2 gene expression downregulation persisted for 15 min into the recovery period, but reversed to upregulation by 2 h. Similar gene expression patterns were also observed for BMP4, although the changes were smaller. The observed changes in BMP gene expression in chick RPE imply dynamic, albeit complex regulation, with the duration of exposure and recovery being critical variables for all three types of visual manipulations. This study provides further evidence for a role of the RPE as an important signal relay linking the retina to the choroid and sclera in eye growth regulation.

The BMP/TGFβ-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via Delta like Canonical Notch Ligand 4 (DLL4). BMP6 modulated VEGF signaling by regulating VEGFR2 expression and acted via Hippo signaling effector TAZ, known to regulate cell survival/proliferation, and to be dysregulated in cancer. In a matrigel plug assay in nude mice BMP6 was further demonstrated to induce angiogenesis. BMP6 is the first member of BMP family found to directly regulate both Hippo signaling and neovessel formation. It may thus serve as a target in pro/anti-angiogenic therapies.

Heterodimeric TGF-β ligands outperform homodimers in a variety of developmental, cell culture, and therapeutic contexts; however, the mechanisms underlying this increased potency remain uncharacterized. Here, we use dorsal–ventral axial patterning of the zebrafish embryo to interrogate the BMP2/7 heterodimer signaling mechanism. We demonstrate that differential interactions with BMP antagonists do not account for the reduced signaling ability of homodimers. Instead, we find that while overexpressed BMP2 homodimers can signal, they require two nonredundant type I receptors, one from the Acvr1 subfamily and one from the Bmpr1 subfamily. This implies that all BMP signaling within the zebrafish gastrula, even BMP2 homodimer signaling, requires Acvr1. This is particularly surprising as BMP2 homodimers do not bind Acvr1 in vitro. Furthermore, we find that the roles of the two type I receptors are subfunctionalized within the heterodimer signaling complex, with the kinase activity of Acvr1 being essential, while that of Bmpr1 is not. These results suggest that the potency of the Bmp2/7 heterodimer arises from the ability to recruit both Acvr1 and Bmpr1 into the same signaling complex.

Mast cells are well established as divergent modulators of inflammation and immunosuppression, but their role in inflammatory bowel disease (IBD) remains to be fully defined. While previous studies have demonstrated a proinflammatory role for mast cells in acute models of chemical colitis, more recent investigations have shown that mast cell deficiency can exacerbate inflammation in spontaneous colitis models, thus suggesting a potential anti-inflammatory role of mast cells in IBD. Here, we tested the hypothesis that in chronic, spontaneous colitis, mast cells are protective. We compared colitis and intestinal barrier function in IL10−/− mice to mast cell deficient/IL10−/− (double knockout (DKO): KitWsh/Wsh × IL10−/−) mice. Compared with IL10−/− mice, DKO mice exhibited more severe colitis as assessed by increased colitis scores, mucosal hypertrophy, intestinal permeability, and colonic cytokine production. PCR array analyses demonstrated enhanced expression of numerous cytokine and chemokine genes and downregulation of anti-inflammatory genes (e.g., Tgfb2, Bmp2, Bmp4, Bmp6, and Bmp7) in the colonic mucosa of DKO mice. Systemic reconstitution of DKO mice with bone marrow-derived mast cells resulted in significant amelioration of IL10−/−-mediated colitis and intestinal barrier injury. Together, the results presented here demonstrate that mast cells exert anti-inflammatory properties in an established model of chronic, spontaneous IBD. Given the previously established proinflammatory role of mast cells in acute chemical colitis models, the present findings provide new insight into the divergent roles of mast cells in modulating inflammation during different stages of colitis. Further investigation of the mechanism of the anti-inflammatory role of the mast cells may elucidate novel therapies.