BACKGROUND: Bone morphogenetic proteins (BMPs) are used in clinical practice for stimulation of bone formation, but often evoke serious complications. Recent studies demonstrated that BMPs involved in early stages of bone formation are species specific. In cattle dominate BMP7, growth differentiation factor 5 (GDF5) and NEL-like protein 1 (NELL1) while in rats BMP2, BMP5 and BMP6. The purpose of the study was to compare the action of the species specific BMPs on the osteoprogenitor cells. Thus, rat osteoprogenitor cells were exposed to one BMP in a high dose and three of them at 1/3 of the former.
METHODS: Isolated rat osteoprogenitor cells were treated in culture with different concentrations of BMP2, BMP5 and BMP6 or with lower concentration of combinations of these cytokines. Activity of alkaline phosphatase, calcium deposition and mRNA level for transcription factor SP7 (osterix) and tissue non-specific alkaline phosphatase (TNAP) served as indicators of BMPs effect.
RESULTS: BMPs stimulated all studied parameters in comparison with control cultures, but no statistically significant differences were observed between the action of a large dose of one cytokine and a combination of cytokines given at lower concentrations.
CONCLUSIONS: Three BMPs used in a low dose exert similar effect as the one used at high dose. Since the BMPs stimulate different receptors and activate different signaling pathways the use of the mixture of properly chosen BMPs at low concentration may give better results than the single one at high concentration and may avoid untoward effects.

OBJECTIVE: This retrospective, practice-based study investigates behaviour management problems (BMPs) in dental care among Finnish children with operated congenital heart disease (CHD).
METHODS: All the heart-operated children born between the years 1997 and 1999 were identified in the national ProCardio database (n = 570). Primary dental care records were requested from this population and were eventually received from 211 patients. Information on gender, diagnosis, number of heart operations and perioperative care were collected from the ProCardio database, and the CHDs were categorised as shunting/stenotic/complex/other defects. Data on BMP/dental fear, oral conscious sedation, dental general anaesthesia (DGA) and past and present caries indices at 6, 12 and 15 years (d/D, dmft/DMFT) were assessed.
RESULTS: Notes on behaviour management problems or dental fear were found in 19% of the study population. BMPs in dental care were more frequent among boys. Children with re-operations, longer post-operative intensive care stay and hospitalisation, and complications had not more BMP than others. Those children diagnosed with syndromes had more BMP often than the rest. Past and present caries experience were significantly associated with BMP, need of oral conscious sedation and DGA. Oral conscious sedation, nitrogen oxide sedation and dental general anaesthesia were used in 17/211, 2/221 and 24/211 CHD patients, respectively.
CONCLUSIONS: Dental caries remains a main factor associated with BMP in the CHD population. Need for oral conscious sedation and DGA were rather common. To maintain a good oral health and to avoid development of BMP, CHD children benefit from focus in health promotion and preventive care.

OBJECTIVE: To test the hypothesis that the use of rhBMP2 in established defects requires additional growth factors such as rhVEGF to accomplish effective bone repair.
METHODS: Horizontal/vertical defects of 2 cm length and 1 cm height were created bilaterally in the alveolar crest of the maxillae of 18 minipigs together with the extraction of all premolar teeth and one molar tooth on both sides. After 3 months of healing, defects were augmented with 0.5 g particulate PDLLA/CaCO3 composite loaded with 400 µg rhBMP2/50 µg rhVEGF165 on one side and 800 µg rhBMP2 on the other in 12 test animals, whereas defects in six control animals were sham operated and left unfilled on one side and augmented with blank carriers on the other. After 4 and 13 weeks, the animals were evaluated each for area of new bone formation (mm²) and bone density (area %).
RESULTS: Augmentations with carriers loaded with 800 g µrhBMP2 failed to induce significantly more bone than in the augmentations with unloaded carrier after 4 and 13 weeks (p = .1000, p = .381). Augmentations with carriers loaded with 400 µg rhBMP2 and 50 µg erhVEGF165 resulted in significantly increased bone formation after 13 weeks (p = .024) compared to blank carriers. Soft tissue in augmentations with combined rhBMP2/rhVEGF165 loading exhibited numerous microvessels compared to soft tissue in augmentations with rhBMP2.
CONCLUSIONS: It is concluded that effective bone regeneration in augmentations of established alveolar ridge defects may require the application of rhVEGF additionally to rhBMP2.

Injecting bone marrow or bone morphogenetic protein 7 (BMP) during core decompression for avascular osteonecrosis (AVN) may improve survival. We hypothesized that adding a complementary technique (injection of BMP and/or non-concentrated bone marrow) to core decompression would reduce the number of patients requiring a subsequent total hip arthroplasty (THA).
We retrospectively reviewed 92 cases from 2003 to 2018 with a minimum of 2 years of follow-up and an average follow-up of 64 months (24-204). Twenty-four patients had a core decompression (CD) (26.1% (24/92)), 25 had a CD associated with reinjection of bone marrow and BMP (rhBMP7) (27.2% (25/92)), and 43 patients had a CD with bone marrow reinjection (46.7% (43/92)).
Hip survival after CD was 66.3% (61/92) at two years and 59.8% (55/92) at 10 years. CD with bone marrow and BMP reinjection had a better hip survival at ten years (HR: 0.492 (CI95%: 0.254-0.952) p = 0.035). A volume of necrosis greater than 30% (HR = 12.97 (CI95 [3.88-43.3] (p < 0.001))) and a Kerboul angle greater than 60° (HR: 12.5 (CI95 [2.84-54.6] (p < 0.001))) were risk factors for a subsequent THA.
CD is an interesting non-invasive technique to preserve the native hip after AVN of the femoral head. Reinjection of bone marrow and/or BMP improved CD hip survival.

Bone morphogenetic proteins (BMPs) are potent osteogenic proteins that induce new bone formation in vivo. However, their effect on bone healing in the trabecular bone surfaces remains challenging. We evaluated the safety and efficacy of recombinant human BMP6 (rhBMP6) applied within an autologous blood coagulum (ABC) in a surgically created wedge defect of the proximal tibia in patients undergoing high tibial osteotomy (HTO) for varus deformity and medial osteoarthritis of the knee. We enrolled 20 HTO patients in a randomized, placebo-controlled, double-blinded phase I/II clinical trial. RhBMP6/ABC (1.0 mg/10 mL ABC prepared from peripheral blood) or placebo (10 mL ABC containing excipients) was administered into the tibial wedge defects. Patients were followed for 0 to 24 months by clinical examination (safety) and computed tomography (CT) and serial radiographic analyses (efficacy). The results show that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 20 patients at 14 weeks after implantation. During the 24 months of follow-up, there were no serious adverse reactions recorded. The CT scans from defects of patients treated with rhBMP6/ABC showed an accelerated bone healing compared with placebo at 9 weeks (47.8 ± 24.1 versus 22.2 ± 12.3 mg/cm3 ; p = 0.008) and at 14 weeks (89.7 ± 29.1 versus 53.6 ± 21.9 mg/cm3 ; p = 0.006) follow-up. Radiographic analyses at weeks 6 and 24 and months 12 and 24 suggested the advanced bone formation and remodeling in rhBMP6/ABC-treated patients. In conclusion, we show that rhBMP6/ABC at a dose of 100 μg/mL accelerated bone healing in patients undergoing HTO without serious adverse events and with a good tolerability compared with placebo alone. Overall, for the first time, a BMP-based osteogenic implant was examined against a placebo for bone healing efficacy in the trabecular bone surface, using an objective bone mineral density measurement system. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

The BMP signaling pathway has been shown to be involved in different aspects of embryonic development across diverse metazoan phyla. Comparative studies on the roles of the BMP signaling pathway provide crucial insights into the evolution of the animal body plans. In this chapter, we present the general workflow on how to investigate the roles of BMP signaling pathway during amphioxus embryonic development. As amphioxus are basal invertebrate chordates, studies on the BMP signaling pathway in amphioxus could elucidate the functional evolution of BMP pathway in the chordate group. Here, we describe methods for animal husbandry, spawning induction, and manipulation of the BMP signaling pathway during embryonic development through drug inhibitors and recombinant proteins. We also introduce an efficient method of using mesh baskets to handle amphioxus embryos for fluorescence immunostaining and multicolor fluorescence in situ hybridization and to assay the effects of manipulating BMP signaling pathway during amphioxus embryogenesis.

METHODS: Prospective cohort study.
OBJECTIVE: To describe the rate of short-term complications following the posterior use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in cervical deformity (CD) surgery.
METHODS: CD patients from 2013 to 2015 were enrolled in a prospective, multicenter database. Patients were divided into those receiving rhBMP-2 (BMP) and no rhBMP-2 (NOBMP). The relationship between BMP use, demographic variables surgical variables, radiographic parameters and complications was evaluated.
RESULTS: A total of 100 patients (47 BMP, 53 NOBMP) were included. Follow-up time averaged 7.6 months (range 3-12 months). An average of 13.6mg of BMP was used per person with 1.49 mg per level. Compared with the NOBMP group, patients in the BMP group were older (P = .03). BMP was more commonly used in patients that and had longer prior fusions (6.0 vs 2.5, P < .01). There were no differences between groups with regards to a history of surgery, Charlson Comorbidity Index, estimated blood loss, operation time, fusion levels, and surgical approach. The maintenance of radiographic parameters at 6-month follow-up was similar. There were no differences in terms of total complication incidence, total complications per person, major complications per person or any specific complication. Linear regression and Pearson correlation analysis did not reveal any strong r2 values (r2 = 0.09, 0.08, 0.06) between the use of BMP and complications (major or operative).
CONCLUSIONS: BMP use was not directly associated with an increased incidence of early complications in this prospective cohort of operative adult CD patients. Its use was associated with increased number of levels instrumented and fused.

Mandibulofacial dysostosis (MFD) is a human developmental disorder characterized by defects of the facial bones. It is the second most frequent craniofacial malformation after cleft lip and palate. Nager syndrome combines many features of MFD with a variety of limb defects. Mutations in SF3B4 (splicing factor 3b, subunit 4) gene, which encodes a component of the pre-mRNA spliceosomal complex, were recently identified as a cause of Nager syndrome, accounting for 60% of affected individuals. Nothing is known about the cellular pathogenesis underlying Nager type MFD. Here we describe the first animal model for Nager syndrome, generated by knocking down Sf3b4 function in Xenopus laevis embryos, using morpholino antisense oligonucleotides. Our results indicate that Sf3b4-depleted embryos show reduced expression of the neural crest genes sox10, snail2 and twist at the neural plate border, associated with a broadening of the neural plate. This phenotype can be rescued by injection of wild-type human SF3B4 mRNA but not by mRNAs carrying mutations that cause Nager syndrome. At the tailbud stage, morphant embryos had decreased sox10 and tfap2a expression in the pharyngeal arches, indicative of a reduced number of neural crest cells. Later in development, Sf3b4-depleted tadpoles exhibited hypoplasia of neural crest-derived craniofacial cartilages, phenocopying aspects of the craniofacial skeletal defects seen in Nager syndrome patients. With this animal model we are now poised to gain important insights into the etiology and pathogenesis of Nager type MFD, and to identify the molecular targets of Sf3b4.

OBJECTIVE: Failure of fusion after a transforaminal lumbar interbody fusion (TLIF) procedure is a challenging problem that can lead to ongoing low-back pain, dependence on pain medication, and inability to return to work. B2A is a synthetic peptide that has proven efficacy in achieving fusion in animal models and may have a better safety profile than bone morphogenetic protein. The authors undertook this study to evaluate the safety and efficacy of B2A peptide-enhanced ceramic granules (Prefix) in comparison with autogenous iliac crest bone graft (ICBG, control) in patients undergoing single-level TLIF.
METHODS: Twenty-four patients with single-level degenerative disorders of the lumbar spine at L2-S1 requiring TLIF were enrolled between 2009 and 2010. They were randomly assigned to 3 groups: a control group (treated with ICBG, n = 9), a Prefix 150 group (treated with Prefix 150 μg/cm(3) granules, n = 8), and a Prefix 750 group (treated with Prefix 750 μg/cm(3) granules, n = 7). Outcome measures included the Oswestry Disability Index (ODI), visual analog pain scale, and radiographic fusion as assessed by CT and dynamic flexion/extension lumbar plain radiographs.
RESULTS: At 12 months after surgery, the radiographic fusion rate was 100% in the Prefix 750 group, 78% in the control group, and 50% in the Prefix 150 group, although the difference was not statistically significant (p = 0.08). At 6 weeks the mean ODI score was 41.0 for the control group, 27.7 for the Prefix 750 group, and 32.2 for the Prefix 150 group, whereas at 12 months the mean ODI was 24.4 for control, 31.1 for Prefix 750, and 29.7 for Prefix 150 groups. Complications were evenly distributed among the groups.
CONCLUSIONS: Prefix appears to provide a safe alternative to autogenous ICBG. Prefix 750 appears to show superior radiographic fusion when compared with autograft at 12 months after TLIF, although no statistically significant difference was demonstrated in this small study. Prefix and control groups both appeared to demonstrate comparable improvements to ODI at 12 months.

Dried plum has been reported to have potent effects on bone in osteopenic animal models, but the mechanisms through which bone metabolism is altered in vivo remain unclear. To address this issue, a study comparing the metabolic response of dried plum to the anabolic agent, parathyroid hormone (PTH), was undertaken. Six month-old female Sprague Dawley rats (n=84) were sham-operated (SHAM) or ovariectomized (OVX) and maintained on a control diet for 6wks until osteopenia was confirmed. Treatments were initiated consisting of a control diet (AIN-93M) supplemented with dried plum (0, 5, 15 or 25%; w/w) or a positive control group receiving PTH. At the end of 6wks of treatment, whole body and femoral bone mineral density (BMD) were restored by the two higher doses of dried plum to the level of the SHAM group. Trabecular bone volume and cortical thickness were also improved with these two doses of dried plum. Dried plum suppressed the OVX-induced increase in bone turnover as indicated by systemic biomarkers of bone metabolism, N-terminal procollagen type 1 (P1NP) and deoxypyridinoline (DPD). Dynamic bone histomorphometric analysis of the tibial metaphysis revealed that dried plum restored the OVX-induced increase in cancellous bone formation rate (BFR) and mineralizing surface (MS/BS) to the SHAM group, but some doses of dried plum increased endocortical mineral apposition rate (MAR). As expected, PTH significantly increased endocortical MAR and BFR, periosteal BFR, and trabecular MAR and BFR beyond that of the OVX and maintained the accelerated rate of bone resorption associated with OVX. Dried plum up-regulated bone morphogenetic protein 4 (Bmp4) and insulin-like growth factor 1 (Igf1) while down-regulating nuclear factor T cell activator 1 (Nfatc1). These findings demonstrate that in the adult osteopenic OVX animal, the effects of dried plum differ from that of PTH in that dried plum primarily suppressed bone turnover with the exception of the indices of bone formation at the endocortical surface.