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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.

Background Efficient and topical delivery of drugs is essential for maximized efficacy and minimized toxicity. In this study, we aimed to design an exosome-based drug delivery platform endowed with the ability of escaping from phagocytosis at non-target organs and controllably releasing drugs at targeted location. Results The swtichable stealth coat CP05-TK-mPEG was synthesized and anchored onto exosomes through the interaction between peptide CP05 and exosomal surface marker CD63. Chlorin e6 (Ce6) was loaded into exosomes by direct incubation. Controllable removal of PEG could be achieved by breaking thioketal (TK) through reactive oxygen species (ROS), which was produced by Ce6 under ultrasound irradiation. The whole platform was called SmartExo. The stealth effects were analyzed in RAW264.7 cells and C57BL/6 mice via tracing the exosomes. To confirm the efficacy of the engineered smart exosomes, Bone morphogenetic protein 7 ( Bmp7 ) mRNA was encapsulated into exosomes by transfection of overexpressing plasmid, followed by stealth coating, with the exosomes designated as SmartExo@Bmp7. Therapeutic advantages of SmartExo@Bmp7 were proved by targeted delivering Bmp7 mRNA to omental adipose tissue (OAT) of obese C57BL/6 mice for browning induction. SmartExo platform was successfully constructed without changing the basic characteristics of exosomes. The engineered exosomes effectively escaped from the phagocytosis by RAW264.7 and non-target organs. In addition, the SmartExo could be uptaken locally on-demand by ultrasound mediated removal of the stealth coat. Compared with control exosomes, SmartExo@Bmp7 effectively delivered Bmp7 mRNA into OAT upon ultrasound irradiation, and induced OAT browning, as evidenced by the histology of OAT and increased expression of uncoupling protein 1 ( Ucp1 ). Conclusions The proposed SmartExo-based delivery platform, which minimizes side effects and maximizing drug efficacy, offers a novel safe and efficient approach for targeted drug delivery. As a proof, the SmartExo@Bmp7 induced local white adipose tissue browning, and it would be a promising strategy for anti-obesity therapy. Graphical Abstract

Background Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder marked by pathological vascular remodeling, predominantly driven by the hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Although bone morphogenetic protein 7 (BMP7) has been implicated in PASMCs dysregulation, the precise upstream mechanisms governing its expression in PH remain elusive. Methods In vitro and in vivo models of hypoxia-induced PH were employed. The mRNA and protein levels of the different molecules were quantified using qRT-PCR and Western blot. The role of BMP7 in PASMCs proliferation, cell cycle progression and apoptosis were assessed using Cell Counting Kit-8 (CCK-8) assays, Western blotting, immunofluorescence, and flow cytometry. Moreover, the epigenetic regulatory mechanisms of BMP7 were elucidated using Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) and quantitative methylation-specific PCR (qMSP). In vivo functional roles of BMP7 were validated using recombinant protein administration and AAV5-mediated gene knockdown in hypoxic mice, with evaluations of hemodynamics, echocardiography, and vascular remodeling. Results Hypoxia significantly upregulated BMP7 expression in PASMCs and lung tissues of PH models. Exogenous BMP7 enhanced PASMCs proliferation, accelerated cell cycle progression and suppressed apoptosis. Conversely, BMP7 knockdown attenuated these pro-proliferative and anti-apoptotic responses. Mechanistically, DNMT1 was downregulated under hypoxia, and its genetic or pharmacological inhibition elevated BMP7 expression, whereas DNMT1 overexpression suppressed BMP7. ChIP-qPCR verified DNMT1 binding to the BMP7 promoter CpG island, and qMSP confirmed that DNMT1 loss reduced BMP7 promoter methylation. Consistent with a pathogenic role, BMP7 knockdown alleviated hypoxia-induced right ventricular hypertrophy and vascular remodeling, while BMP7 supplementation exacerbated these phenotypes. Conclusions Our study unveils the DNMT1-BMP7 axis as a critical epigenetic pathway in PH. Hypoxia-induced DNMT1 downregulation derepresses BMP7 via promoter hypomethylation, driving PASMCs proliferation and pathological vascular remodeling. Targeting this axis may offer novel therapeutic strategies for PH.

Localized and release-controlled delivery systems for the sustained expression of the biologic potency of rhBMPs are essential. A substantial number of biomaterials have been investigated thus far. Most fail after implantation or administration mainly due to either being too soft, difficult to control and/or stabilize mechanically. In the second part of this review, we review a representative selection of rhBMP-2 and rhBMP-7 carrier materials and delivery systems ranging from simple nano/microparticles to complex 3-D scaffolds in sites of orthopaedic and craniofacial bone regeneration and repair.

Background There are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra-articular recombinant human BMP-7 (bone morphogenetic protein-7) has reparative effects on cartilage, as well as on symptoms of joint pain. The objective of this study was to determine the safety and tolerability as well as dose-limiting toxicity and maximal tolerated dose of intra-articular BMP-7. The secondary objectives were to determine the effect on symptomatic responses through 24 weeks. Methods This was a Phase 1, double-blind, randomized, multi-center, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts in participants with knee OA. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active (intra-articular BMP-7) to placebo ratio. Eligible participants were persons with symptomatic radiographic knee OA over the age of 40. The primary objective of this study was to determine the safety and tolerability of BMP-7 including laboratory assessments, immunogenicity data and radiographic assessments. Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria. Results The mean age of participants was 60 years and 73% were female. All 33 participants who were enrolled completed the study and most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. The 1 mg BMP-7 group showed a higher frequency of injection site pain and there was no ectopic bone formation seen on plain x-rays. By week 12, most participants in both the BMP-7 and placebo groups experienced a 20% improvement in pain and overall the BMP-7 group was similar to placebo with regard to this measurement. In the participants who received 0.1 mg and 0.3 mg BMP-7, there was a trend toward greater symptomatic improvement than placebo. The other secondary endpoints showed similar trends including the OARSI responder criteria for which the BMP-7 groups had more responders than placebo. Conclusions There was no dose limiting toxicity identified in this study. The suggestion of a symptom response, together with the lack of dose limiting toxicity provide further support for the continued development of this product for the treatment of osteoarthritis.

Bone morphogenetic proteins (BMPs) are considered important regulators of neural development. However, results mainly from a wide set of in vitro gain-of-function experiments are conflicting since these show that BMPs can act either as inhibitors or promoters of neurogenesis. Here, we report a specific and non-redundant role for BMP7 in cortical neurogenesis in vivo using knockout mice. Bmp7 is produced in regions adjacent to the developing cortex; the hem, meninges, and choroid plexus, and can be detected in the cerebrospinal fluid. Bmp7 deletion results in reduced cortical thickening, impaired neurogenesis, and loss of radial glia attachment to the meninges. Subsequent in vitro analyses of E14.5 cortical cells revealed that lack of Bmp7 affects neural progenitor cells, evidenced by their reduced proliferation, survival and self-renewal capacity. Addition of BMP7 was able to rescue these proliferation and survival defects. In addition, at the developmental stage E14.5 Bmp7 was also required to maintain Ngn2 expression in the subventricular zone. These data demonstrate a novel role for Bmp7 in the embryonic mouse cortex: Bmp7 nurtures radial glia cells and regulates fundamental properties of neural progenitor cells that subsequently affect Ngn2-dependent neurogenesis.

Background The Pacific abalone, Haliotis discus hannai , is the most important cultivated abalone in China. Improving abalone muscle growth and increasing the rate of growth are important genetic improvement programs in this industry. MicroRNAs are important small noncoding RNA molecules that regulate post-transcription gene expression. However, no miRNAs have been reported to regulate muscle growth in H. discus hannai . Results we profiled six small RNA libraries for three large abalone individuals (L_HD group) and three small individuals (S_HD group) using RNA sequencing technology. A total of 205 miRNAs, including 200 novel and 5 known miRNAs, were identified. In the L_HD group, 3 miRNAs were up-regulated and 7 were down-regulated compared to the S_HD specimens. Bioinformatics analysis of miRNA target genes revealed that miRNAs participated in the regulation of cellular metabolic processes, the regulation of biological processes, the Wnt signaling pathway, ECM-receptor interaction, and the MAPK signaling pathway, which are associated with regulating growth. Bone morphogenetic protein 7 (BMP7) was verified as a target gene of hdh-miR-1984 by a luciferase reporter assay and we examined the expression pattern in different developmental stages. Conclusion This is the first study to demonstrate that miRNAs are related to the muscle growth of H. discus hannai . This information could be used to study the mechanisms of abalone muscle growth. These DE-miRNAs may be useful as molecular markers for functional genomics and breeding research in abalone and closely related species.

Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by histone deacetylase (HDAC) inhibitors via epigenetic modification to enhance bone morphogenetic protein 7 (BMP-7) expression. Cisplatin upregulated the activity of HDAC2 in the kidney. Inhibition of HDAC with clinically used trichostatin A (TSA) or valproic acid (VPA) suppressed cisplatin-induced kidney injury and epithelial cell apoptosis. Overexpression of HDAC2 promotes CP-treated tubular epithelium cells apoptosis. Chromatin immunoprecipitation assay clearly detected HDAC2 assosiation with BMP-7 promoter. Western blot and immunofluorescence results demonstrated that the expression of BMP-7 was clearly induced by TSA or VPA in vivo and in vitro . Interestingly, administration of recombinant BMP-7 (rhBMP-7) reduced cisplatin-induced kidney dysfunction. Moreover, BMP-7 treatment suppressed epithelial cell apoptosis and small interfering RNA-based knockdown of BMP-7 expression abolished HDAC inhibitors suppression of epithelial cell apoptosis in vitro . Results of current study indicated that TSA or VPA inhibited apoptosis of renal tubular epithelial cells via promoting the level of BMP-7 epigenetically through targeting HDAC2. Hence, HDAC inhibitors could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity.

金沢大学医薬保健研究域医学系 The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3 -/- mice, which model Alport syndrome. Ablation of Usag1 in Col4a3-/- mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3-/- mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.

Bone morphogenetic proteins (BMPs) are associated with the prognosis of various types of adult cancers. However, the expressions and prognosis of BMPs in pediatric neuroblastoma remain unclear. Six publicly available neuroblastoma cohorts were downloaded for bioinformatics analysis. The prognosis of BMPs in neuroblastoma was determined using cox regression analysis and Kaplan-Meier survival analysis. Our study revealed that, compared to other BMP family members, BMP1, BMP7 and BMP8B were highly expressed in neuroblastoma. However, only BMP7 was associated with the prognosis of neuroblastoma in all six neuroblastoma cohorts. Higher BMP7 expression was associated with the shorted event free survival and overall survival of neuroblastoma. The prognosis of BMP7 in neuroblastoma was independent of age and MYCN amplification. The expressions of BMP7 were higher in neuroblastoma patients with MYCN amplification or age ≥ 18months or in stage 4 neuroblastoma. Moreover, higher BMP7 was associated with the shorted event free survival and overall survival of MYCN amplified or stage 4 neuroblastoma. At last, we found that breast cancer metastasis suppressor 1 (BRMS1) was correlated with BMP7 expression. However, in contrast with the suppressor role of BRMS1 in adult cancers, BRMS1 was significantly associated with the unfavorable clinical outcomes of neuroblastoma. Overall, our analysis the demonstrated correlations between BMPs and clinical features of neuroblastoma and provided unique therapeutic targets for neuroblastoma treatments. BMP7 was a prognostic maker of neuroblastoma.