Detection of GDF11 by using a Ti3C2-MXene-based fiber SPR biosensor.

In the research of resistant aging, the concentration of Growth differentiation factor-11(GDF11) is an indispensable parameter. So the accurate detection of GDF11 is very important in life science and medical cosmetology. Hereby, we proposed and demonstrated a simple method to detect low concentration GDF11 by using fiber surface plasmon resonance (SPR) sensor decorated with two-dimension (2D) material Ti3C2-MXene and gold nanosphere. The sensitivity of the fiber SPR sensor was increased to be 4804.64nm/RIU. After functionalized with GDF11 antibody, the fiber SPR sensor could specifically recognize GDF11, and the limit of detection (LOD) can reach 0.577pg/L which is 100 times lower than that of single-molecule ELISA method.

Sostdc1 Regulates NK Cell Maturation and Cytotoxicity.

NK cells are innate-like lymphocytes that eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified roles for sclerostin domain-containing-1 (Sostdc1) in NK cell development and function. Sostdc1-knockout (Sostdc1 -/-) mice display a progressive accumulation of transitional NK cells (tNKs) (CD27+CD11b+) with age, indicating a partial developmental block. The NK cell Ly49 repertoire in Sostdc1 -/- mice is also changed. Lower frequencies of Sostdc1 -/- splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I+, G2+, H+, and D+ populations were universally decreased at the most mature (CD27-CD11b+) stage. We hypothesized that the Ly49 repertoire in Sostdc1 -/- mice would correlate with NK killing ability and observed that Sostdc1-/- NK cells are hyporesponsive against MHC class I-deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN-γ expression to controls. Consistent with Sostdc1's known role in Wnt signaling regulation, Tcf7 and Lef1 levels were higher in Sostdc1 -/- NK cells. Expression of the NK development gene Id2 was decreased in Sostdc1-/- immature NK and tNK cells, but Eomes and Tbx21 expression was unaffected. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both nonhematopoietic and hematopoietic sources. Taken together, these data support a role for Sostdc1 in the regulation of NK cell maturation and cytotoxicity, and identify potential NK cell niches.

Combined antisclerostin antibody and parathyroid hormone (1-34) synergistically enhance the healing of bone defects in ovariectomized rats.

Osteoporotic bones heal more slowly and ineffectively than normal bones. A combination of antibodies against sclerosing protein (Scl-Ab), and parathyroid hormone 1-34 (PTH 1-34) may improve healing. A standard osteoporotic rat model was established 12 weeks after bilateral ovarian resection (OVX). Bone defects were created in the right femora of 80 rats, which were randomly divided into 4 groups: control, Scl-Ab (25 mg/kg twice weekly), PTH (60 µg/kg of PTH 1-34 three times a week) and PTH plus Scl-Ab. After 12 weeks of treatment the rats were sacrificed and blood and the distal femora were harvested for biochemical evaluation, histology, microcomputed tomography and biomechanical testing. Compared to the control group, monotherapy and combination therapy with PTH and/or Scl-Ab promoted the formation of new bone, enhanced maximum femoral loading and increased the levels of procollagen type I N­terminal propeptide (PINP) and osteocalcin. The administration of PTH + Scl-Ab maximally enhanced bone defect healing. Combination treatment was better than either treatment alone, indicating a synergistic effect.

Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma.

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM.

The zinc finger protein CG12744 is essential for differentiation and regeneration after infection in the adult Drosophila midgut.

Pluripotent stem cell activity is essential to maintain regeneration and homeostasis in the Drosophila midgut following environmental challenges. Although multiple pathways have been implicated in epithelial renewal, the underlying regulatory mechanisms and correlations between relevant genes and pathways remain elusive. In this study, we show that the zinc finger protein CG12744 plays an important role in the differentiation and regeneration of epithelial cells in response to oral infection with Erwinia carotovora carotovora 15. Knocking down CG12744 in enteroblasts decreased the post-infection proportion of enteroblasts and enterocytes and increased the post-infection number of enteroendocrine cells. In addition, in precursors, CG12744 affected the Osa, jun-N-terminal kinase and bone morphogenetic protein signaling pathways to control enterocyte differentiation. Finally, CG12744 maintained epithelial architecture and cell fate in enterocytes following an acute infectious challenge.

Anabolic Therapy for the Treatment of Osteoporosis in Childhood.

PURPOSE OF REVIEW: Numerous forms of osteoporosis in childhood are characterized by low bone turnover (for example, osteoporosis due to neuromuscular disorders and glucocorticoid exposure). Anti-resorptive therapy, traditionally used to treat osteoporosis in the young, is associated with further reductions in bone turnover, raising concerns about the long-term safety and efficacy of such therapy. These observations have led to increasing interest in the role of anabolic therapy to treat pediatric osteoporosis. RECENT FINDINGS: While growth hormone and androgens appears to be relatively weak anabolic modulators of bone mass, emerging therapies targeting bone formation pathways (anti-transforming growth factor beta antibody and anti-sclerostin antibody) hold considerable promise. Teriparatide remains an attractive option that merits formal study for patients post-epiphyseal fusion, although it must be considered that adult studies have shown its effect is blunted when administered following bisphosphonate therapy. Mechanical stimulation of bone through whole body vibration therapy appears to be much less effective than bisphosphonate therapy for treating osteoporosis in children. New anabolic therapies which target important pathways in skeletal metabolism merit further study in children, including their effects on fracture risk reduction and after treatment discontinuation.

Anabolic Strategies to Augment Bone Fracture Healing.

PURPOSE OF REVIEW: The development of therapeutics that target anabolic pathways involved in skeletogenesis is of great importance with regard to disease resulting in bone loss, or in cases of impaired bone repair. This review aims to summarize recent developments in this area. RECENT FINDINGS: A greater understanding of how drugs that modulate signaling pathways involved in skeletogenesis exert their efficacy, and the molecular mechanisms resulting in bone formation has led to novel pharmacological bone repair strategies. Furthermore, crosstalk between pathways and molecules has suggested signaling synergies that may be exploited for enhanced tissue formation. The sequential pharmacological stimulation of the molecular cascades resulting in tissue repair is a promising strategy for the treatment of bone fractures. It is proposed that a therapeutic strategy which mimics the natural cascade of events observed during fracture repair may be achieved through temporal targeting of tissue repair pathways.

Anabolic Therapies in Osteoporosis and Bone Regeneration.

Osteoporosis represents the most common bone disease worldwide and results in a significantly increased fracture risk. Extrinsic and intrinsic factors implicated in the development of osteoporosis are also associated with delayed fracture healing and impaired bone regeneration. Based on a steadily increasing life expectancy in modern societies, the global implications of osteoporosis and impaired bone healing are substantial. Research in the last decades has revealed several molecular pathways that stimulate bone formation and could be targeted to treat both osteoporosis and impaired fracture healing. The identification and development of therapeutic approaches modulating bone formation, rather than bone resorption, fulfils an essential clinical need, as treatment options for reversing bone loss and promoting bone regeneration are limited. This review focuses on currently available and future approaches that may have the potential to achieve these aims.

The effects of sclerostin antibody plus parathyroid hormone (1-34) on bone formation in ovariectomized rats.

Previous studies have demonstrated the effects of sclerostin antibody (Scl-Ab) and parathyroid hormone (1-34, PTH) on healing in osteoporosis; however, reports about the combined effects of Scl-Ab plus PTH on osteoporosis are limited. This study was designed to investigate the impact of combined treatment with Scl-Ab and PTH on osteoporosis healing in ovariectomized (OVX) rats. After bilateral ovariectomy, 12 weeks were allowed to pass for the establishment of standard conditions for osteoporosis in animal models. The rats then randomly received a vehicle (control), Scl-Ab (25 mg/kg body weight, twice weekly), PTH (60 µg/kg, three times per week) or PTH plus Scl-Ab until death at 12 weeks. The blood and distal femurs of the rats were harvested for evaluation. The results of treatment for osteoporosis were evaluated by serum analysis, histology, microcomputed tomography (micro-CT) and biomechanical tests. Results from this study indicated that PTH + Scl-Ab had stronger effects on the prevention and treatment of osteoporosis than either of the monotherapies in OVX rats. The PTH + Scl-Ab produced the strongest effects on bone volume fraction (BV/TV), bone trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular spacing (Tb.Sp), bone mineral density (BMD) and strength of distal femurs and increased the levels of procollagen type I N­terminal propeptide (PINP) and osteocalcin. In contrast, monotherapy with PTH or Scl-Ab showed no differences between treated groups in the assessment of the metaphysis of contralateral femurs by histology, serum, biomechanical tests and micro-CT. These results seem to indicate that Scl-Ab plus PTH has an additive effect on osteoporosis in OVX rats.

Systemic inhibition of BMP1-3 decreases progression of CCl4-induced liver fibrosis in rats.

Liver fibrosis is a progressive pathological process resulting in an accumulation of excess extracellular matrix proteins. We discovered that bone morphogenetic protein 1-3 (BMP1-3), an isoform of the metalloproteinase Bmp1 gene, circulates in the plasma of healthy volunteers and its neutralization decreases the progression of chronic kidney disease in 5/6 nephrectomized rats. Here, we investigated the potential role of BMP1-3 in a chronic liver disease. Rats with carbon tetrachloride (CCl4)-induced liver fibrosis were treated with monoclonal anti-BMP1-3 antibodies. Treatment with anti-BMP1-3 antibodies dose-dependently lowered the amount of collagen type I, downregulated the expression of Tgfb1, Itgb6, Col1a1, and Acta2 and upregulated the expression of Ctgf, Itgb1, and Dcn. Mehanistically, BMP1-3 inhibition decreased the plasma levels of transforming growth factor beta 1(TGFß1) by prevention of its activation and lowered the prodecorin production further suppressing the TGFß1 profibrotic effect. Our results suggest that BMP1-3 inhibitors have significant potential for decreasing the progression of fibrosis in liver cirrhosis.

Sclerostin Antibody Increases Callus Size and Strength but does not Improve Fracture Union in a Challenged Open Rat Fracture Model.

Open fractures remain a challenge in orthopedics. Current strategies to intervene are often inadequate, particularly in severe fractures or when treatment is delayed. Sclerostin is a negative regulator of bone growth and sclerostin-neutralizing antibodies (Scl-Ab) can increase bone mass and strength. The application of these antibodies to improve orthopedic repair has shown varied results, and may be dependent on the location and severity of the bony injury. We examined Scl-Ab treatment within an established rat osteotomy model with periosteal stripping analogous to open fracture repair. In one study, Scl-Ab was given 25 mg/kg bi-weekly, either from the time of fracture or from 3 weeks post-fracture up to an end-point of 12 weeks. A second study treated only delayed union open fractures that did not show radiographic union by week 6 post-fracture. Outcome measures included radiographic union, microCT analysis of bone volume and architecture, and histology. In the first study, Scl-Ab given from either 0 or 3 weeks significantly improved callus bone volume (+52%, p < 0.05 and +58%, p < 0.01) at 12 weeks, as well as strength (+48%, p < 0.05 and +70%, p < 0.05). Despite these improvements, union rate was not changed. In the second study treating only established delayed fractures, bony callus volume was similarly increased by Scl-Ab treatment; however, this did not translate to increased biomechanical strength or union improvement. Sclerostin antibody treatment has limited effects on the healing of challenging open fractures with periosteal stripping, but shows the greatest benefits on callus size and strength with earlier intervention.

Comparison of tissue transglutaminase 2 and bone biological markers osteocalcin, osteopontin and sclerostin expression in human osteoporosis and osteoarthritis.

Osteoporosis (OP) and osteoarthritis (OA) are the most common joint diseases, with a high incidence in the elderly population. OP is characterized by trabecular bone remodeling and reabsorption, whereas articular cartilage and subchondral bone remodeling are major features of OA. Although classically considered as independent or even conflicting processes, clinical coexistence of OP and OA was recently described. Transglutaminase 2 (TG2) expression is considered a biomarker of OA, but its role in osteoporotic bone remodeling is still uncertain. We investigated TG2 and bone biological markers (Osteocalcin, Osteopontin, and Sclerostin) in osteoporotic and osteoarthritic osteocartilagineous tissue (n = 54) and human chondrocyte cultures in vitro by immunohistochemistry, immunofluorescence and RT-PCR. Histomorphometric evaluation of bone trabecular remodeling was also performed. In cartilage, TG2 expression was faint in control and OP and significantly less than in OA and OP + OA chondrocytes; the opposite was found for Osteocalcin, whereas Osteopontin and Sclerostin expression was similar. In the subchondral trabecular bone, osteocytes/osteoblasts TG2 expression was slight and similar comparing control, OP, OA, and OP + OA group, whereas Osteocalcin and Osteopontin expression was lower in OP compared to control, OA and OP + OA. Increased TG2 and reduced Osteocalcin expression were maintained in human osteoarthritic chondrocytes in vitro. Histomorphometric analysis confirmed reduced trabecular bone mass in OP and OP + OA compared with OA patients. TG2 represented a suitable biomarker of osteoarthritic chondrocyte activation, whereas osteocalcin and osteopontin characterized osteoporotic osteocyte/osteoblast changes; differences were lost in OP + OA patients, suggesting careful consideration when coexistence of the two diseases occurs.

TGF-ß1, but not bone morphogenetic proteins, activates Smad1/5 pathway in primary human macrophages and induces expression of proatherogenic genes.

Macrophages are responsible for the control of inflammation and healing, and their malfunction results in cardiometabolic disorders. TGF-ß is a pleiotropic growth factor with dual (protective and detrimental) roles in atherogenesis. We have previously shown that in human macrophages, TGF-ß1 activates Smad2/3 signaling and induces a complex gene expression program. However, activated genes were not limited to known Smad2/3-dependent ones, which prompted us to study TGF-ß1-induced signaling in macrophages in detail. Analysis of Id3 regulatory sequences revealed a novel enhancer, located between +4517 and 4662 bp, but the luciferase reporter assay demonstrated that this enhancer is not Smad2/3 dependent. Because Id3 expression is regulated by Smad1/5 in endothelial cells, we analyzed activation of Smad1/5 in macrophages. We demonstrate here for the first time, to our knowledge, that TGF-ß1, but not BMPs, activates Smad1/5 in macrophages. We show that an ALK5/ALK1 heterodimer is responsible for the induction of Smad1/5 signaling by TGF-ß1 in mature human macrophages. Activation of Smad1/5 by TGF-ß1 induces not only Id3, but also HAMP and PLAUR, which contribute to atherosclerotic plaque vulnerability. We suggest that the balance between Smad1/5- and Smad2/3-dependent signaling defines the outcome of the effect of TGF-ß on atherosclerosis where Smad1/5 is responsible for proatherogenic effects, whereas Smad2/3 regulate atheroprotective effects of TGF-ß.

Commensal Bacteria-induced Interleukin 1ß (IL-1ß) Secreted by Macrophages Up-regulates Hepcidin Expression in Hepatocytes by Activating the Bone Morphogenetic Protein Signaling Pathway.

The liver hormone hepcidin is the central regulator of systemic iron metabolism. Its increased expression in inflammatory states leads to hypoferremia and anemia. Elucidation of the mechanisms that up-regulate hepcidin during inflammation is essential for developing rational therapies for this anemia. Using mouse models of inflammatory bowel disease, we have shown previously that colitis-associated hepcidin induction is influenced by intestinal microbiota composition. Here we investigate how two commensal bacteria, Bifidobacterium longum and Bacteroides fragilis, representative members of the gut microbiota, affect hepcidin expression. We found that supernatants of a human macrophage cell line infected with either of the bacteria up-regulated hepcidin when added to a human hepatocyte cell line. This activity was abrogated by neutralization of IL-1ß. Moreover, purified IL-1ß increased hepcidin expression when added to the hepatocyte line or primary human hepatocytes and when injected into mice. IL-1ß activated the bone morphogenetic protein (BMP) signaling pathway in hepatocytes and in mouse liver, as indicated by increased phosphorylation of small mothers against decapentaplegic proteins. Activation of BMP signaling correlated with IL-1ß-induced expression of BMP2 in human hepatocytes and activin B in mouse liver. Treatment of hepatocytes with two different chemical inhibitors of BMP signaling or with a neutralizing antibody to BMP2 prevented IL-1ß-induced up-regulation of hepcidin. Our results clarify how commensal bacteria affect hepcidin expression and reveal a novel connection between IL-1ß and activation of BMP signaling. They also suggest that there may be differences between mice and humans with respect to the mechanism by which IL-1ß up-regulates hepcidin.

[Newly developed drugs to improve bone strength].

Drugs for the treatment of osteoporosis improve bone strength by inhibiting bone resorption or stimulating bone formation. New drugs already using some action mechanism such as bisphosphonate or parathyroid hormone-related peptide analog are being developed in Japan. In addition, new drugs with new action mechanisms such as cathepsin K inhibitor or anti-sclerostin antibody are also being developed and it has been reported that they have good potential to increase bone mineral density.

Sclerostin and skeletal health.

Sclerostin is a cysteine-knot glycoprotein product of the SOST gene, predominately expressed by osteocytes, that is a regulator of osteoblastic bone formation. When sclerostin binds to its low-density lipoprotein receptor-related proteins 5 and 6 on the cell membrane of osteoblasts, it inhibits canonical Wnt/ß-catenin signaling and reduces osteoblastic bone formation. Sclerostin was first identified in the study of two rare autosomal recessive disorders, sclerosteosis and van Buchem disease, which are associated with absent or reduced levels of sclerostin. Although homozygote patients with these disorders have serious adverse clinical consequences due to excessive bone growth, heterozygote patients have a normal phenotype, high bone mass, and very low risk of fractures. This has led to the concept that downregulation of sclerostin might be effective in the treatment of osteoporosis. Several humanized monoclonal antibodies to sclerostin, including romosozumab and blosozumab, are now in clinical development. Preliminary data show that these agents result in a transient increase in bone formation markers, a sustained decrease in bone resorption markers, and a robust increase in bone mineral density. If any of these agents are found to reduce fracture risk with a favorable safety profile, it will expand the options for osteoanabolic therapy for patients at high risk for fractures.

[Bone and Nutrition. Sclerostin and bone metabolism].

Osteocytes orchestrate bone resorption and bone formation by controlling osteoclast and osteoblast activity. On the other hand, osteocytes secret FGF23 (fibroblast growth factor 23), FGF23 acts on the kidney to control phosphate homeostasis. Sclerostin is also released from osteocytes and it regulated osteoblast activity through Wnt/ß-catenin pathway. Therefore, an antibody that targets sclerostin is currently in phase- III clinical trials for the treatment of osteoporosis and it is expected as new therapeutics.

Inhibitors of sclerostin: emerging concepts.

PURPOSE OF REVIEW: Recent data suggest that inhibitors of sclerostin, an osteocyte-produced Wnt signaling pathway antagonist, can stimulate bone formation. This review provides rationale and summarizes recent evidence supporting this novel approach to skeletal anabolism. RECENT FINDINGS: Data from numerous preclinical models in rodents and monkeys consistently demonstrate that antisclerostin monoclonal antibody (Scl-Ab) treatment leads to improvements in bone mass and strength, as well as enhanced fracture repair. Delivery of Scl-Ab therapy either subcutaneously or intravenously in phase 1 and 2 human clinical trials demonstrates short-term anabolic responses in excess of those seen with teriparatide, the only currently available anabolic skeletal agent. Gains have been primarily at central (spine and hips) versus peripheral (wrist) sites. Strikingly, Scl-Ab treatment appears to both stimulate bone formation and inhibit bone resorption in humans. If proven, Scl-Ab would be the first pharmacologic agent with such dual properties. Data on fractures are not yet available. SUMMARY: Scl-Ab therapy represents a novel pharmacologic approach to skeletal anabolism. Although many questions remain before Scl-Ab treatment can be introduced into clinical practice, phase 3 human clinical trials are currently underway and could provide the necessary data to bring this exciting class of skeletal anabolic agents to patient care.

Serum levels of novel noggin and sclerostin-immune complexes are elevated in ankylosing spondylitis.

BACKGROUND: Unravelling the basis of joint inflammation and ankylosis represents a major challenge in ankylosing spondylitis (AS) research. As noggin (NOG) and sclerostin (SOST) have recently been associated with the disease process in mouse and human studies, respectively, we explored the immune responses to these two molecules in AS. METHODS: Immune complexes (IC) composed of IgG autoantibodies to NOG and SOST were detected by immunoprecipitation and Western blot analyses. Epitope-specific IgG were measured using peptide-binding ELISA. Serum samples were obtained from healthy controls and patients with AS, mechanical back pain (MBP) and inflammatory bowel disease (IBD) with or without concomitant AS. RESULTS: NOG and SOST-IgG IC were present in NOG-treated and untreated ank/ank (progressive ankylosis), but not in wild-type mice. Higher than normal levels of NOG and SOST-IgG IC are present in AS sera (p<0.001). We showed a SOST peptide (SOST-S146, with homology to a bacterial glycotransferase peptide) binds to a NOG peptide (NOG-N54), which contains a N-glycosylation site. AS patients have higher levels of IgG recognising the NOG-N54 and SOST-S146 peptides compared to the levels in normal controls, IBD and MBP patients (one way analysis of variance p<0.0001). CONCLUSIONS: This is the first report showing IgG autoantibodies to NOG and SOST in normal individuals, and higher levels of NOG and/or SOST-IgG IC probably contribute to neo-ossification in AS patients. These novel findings hold the promise of earlier diagnosis, better management of AS with comorbidities and new therapeutic approaches to modulate ankylosis in AS.

Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength.

UNLABELLED: Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI-causing defect. INTRODUCTION: Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1. METHODS: Six-month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2×/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed. RESULTS: Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength. CONCLUSION: Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI.