The bone morphogenetic protein (BMP) and Wnt signaling pathways both contribute essential roles in regulating bone mass. However, the molecular interactions between these pathways in osteoblasts are poorly understood. We recently reported that osteoblast-targeted conditional knockout (cKO) of BMP receptor type IA (BMPRIA) resulted in increased bone mass during embryonic development, where diminished expression of Sost as a downstream effector of BMPRIA resulted in increased Wnt/β-catenin signaling. Here, we report that Bmpr1a cKO mice exhibit increased bone mass during weanling stages, again with evidence of enhanced Wnt/β-catenin signaling as assessed by Wnt reporter TOPGAL mice and TOPFLASH luciferase. Consistent with negative regulation of the Wnt pathway by BMPRIA signaling, treatment of osteoblasts with dorsomorphin, an inhibitor of Smad-dependent BMP signaling, enhanced Wnt signaling. In addition to Sost, Wnt inhibitor Dkk1 also was downregulated in cKO bone. Expression levels of Dkk1and Sost were upregulated by BMP2 treatment and downregulated by Noggin. Moreover, expression of a constitutively active Bmpr1a transgene in mice resulted in the upregulation of both Dkk1 and Sost and partially rescued the Bmpr1a cKO bone phenotype. These effectors are differentially regulated by mitogen-activated protein kinase (MAPK) p38 because pretreatment of osteoblasts with SB202190 blocked BMP2-induced Dkk1 expression but not Sost. These results demonstrate that BMPRIA in osteoblasts negatively regulates endogenous bone mass and Wnt/β-catenin signaling and that this regulation may be mediated by the activities of Sost and Dkk1. This study highlights several interactions between BMP and Wnt signaling cascades in osteoblasts that may be amenable to therapeutic intervention for the modification of bone mass density. © 2010 American Society for Bone and Mineral Research

/pdf/wnt-inhibitors-dkk1-and-sost-are-downstream-targets-of-bmp-2bnnvd83cd.pdf

Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts.

Bone morphogenetic proteins (BMPs) are known as ectopic bone inducers. The FDA approved BMPs (BMP2 and BMP7) for clinical use. However, direct effects of BMPs on endogenous bone metabolism are not yet well known. We conditionally disrupted BMP receptor type IA (BMPRIA) in osteoblasts during weanling and adult stages to show the impact of BMP signaling on endogenous bone modeling and remodeling. Cre recombination was detected in immature osteoblasts in the periosteum, osteoblasts, and osteocytes but not in chondrocytes and osteoclasts after tamoxifen administration. Bmpr1a conditional knockout mice (cKO) showed increased bone mass primarily in trabecular bone at P21 and 22 wk as determined by H&E staining. Vertebrae, tails, and ribs showed increased radiodensity at 22 wk, consistent with a significant increase in BMD. Both μCT and histomorphometry showed an increase in trabecular BV/TV and thickness of cKO adult bones, whereas osteoclast number, bone formation rate, and mineral apposition rate were decreased. Expression levels of bone formation markers (Runx2 and Bsp), resorption markers (Mmp9, Ctsk, and Tracp), and Rankl were decreased, and Opg was increased in adult bones, resulting in a reduction in the ratio of Rankl to osteoprotegerin (Opg). The reduction in osteoclastogenesis through the RANKL–OPG pathway was also observed in weanling stages and reproduced in newborn calvaria culture. These results suggest that Bmpr1a cKO increased endogenous bone mass primarily in trabecular bone with decreased osteoclastogenesis through the RANKL–OPG pathway. We conclude that BMPRIA signaling in osteoblasts affects both bone formation and resorption to reduce endogenous bone mass in vivo.

Disruption of BMP Signaling in Osteoblasts Through Type IA Receptor (BMPRIA) Increases Bone Mass

Diseases such as osteoporosis are associated with reduced bone mass. Therapies to prevent bone loss exist, but there are few that stimulate bone formation and restore bone mass. Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily, which act as pleiotropic regulators of skeletal organogenesis and bone homeostasis. Ablation of the BMPR1A receptor in osteoblasts increases bone mass, suggesting that inhibition of BMPR1A signaling may have therapeutic benefit. The aim of this study was to determine the skeletal effects of systemic administration of a soluble BMPR1A fusion protein (mBMPR1A–mFc) in vivo. mBMPR1A–mFc was shown to bind BMP2/4 specifically and with high affinity and prevent downstream signaling. mBMPR1A–mFc treatment of immature and mature mice increased bone mineral density, cortical thickness, trabecular bone volume, thickness and number, and decreased trabecular separation. The increase in bone mass was due to an early increase in osteoblast number and bone formation rate, mediated by a suppression of Dickkopf-1 expression. This was followed by a decrease in osteoclast number and eroded surface, which was associated with a decrease in receptor activator of NF-κB ligand (RANKL) production, an increase in osteoprotegerin expression, and a decrease in serum tartrate-resistant acid phosphatase (TRAP5b) concentration. mBMPR1A treatment also increased bone mass and strength in mice with bone loss due to estrogen deficiency. In conclusion, mBMPR1A–mFc stimulates osteoblastic bone formation and decreases bone resorption, which leads to an increase in bone mass, and offers a promising unique alternative for the treatment of bone-related disorders.

https://www.pnas.org/content/pnas/109/30/12207.full.pdf

A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jor.21065

Mesenchymal stem cells accelerate bone allograft incorporation in the presence of diabetes mellitus

The present invention relates to novel bone compositions for locally delivering a therapeutic agent to the site of a bone defect. Therapeutic agents may promote repair of the bone defect and/or treat conditions or disorders such as pain, inflammation, cancer, and infection. The compositions include calcium phosphate cements and a demineralized bone matrix or a collagen sponge. The compositions are useful for implantation in a patient at the site of a bone defect.

Methods, systems, and compositions for promoting bone growth

The bone morphogenetic proteins (BMPs) carry a crucial role in bone formation and bone healing. Previous studies have identified the osteoinductive capabilities of demineralized bone matrix (DBM) and the individual factor osteogenic protein-1 (OP-1), also known as BMP-7. The purpose of this study is to identify the short-term healing effects of targeted drug delivery of demineralized bone matrix and osteogenic protein-1 following bony trauma in terms of mechanical strength and histological changes. Animals in Group 1 acted as the control and Group 2 received a unicortical drill defect and placement of a calcined tricalcium phosphate lysine (TCPL) capsule containing antibiotic (sham). Group 3 and 4 animals had a created drill defect and received a TCPL carrier containing antibiotic along with DBM or OP-1, respectively. After 2 weeks post-implantation, animals in each group were sacrificed before the retrieval of the bone. The femurs were analyzed biomechanically for return of strength and histologically for bone growth. The average rupture strength for the femurs of the control group was shown to be significantly higher than all other groups (p<0.001 compared to sham, DBM, and OP-1). There was no significant difference between the two treatment groups (p=0.984) and there was no significant difference between the sham and DBM or OP-1 treated groups (p=0.908 and p=0.991, respectively). Analysis of the gross specimens showed minimal signs of bone regeneration at the defect site for both DBM and OP-l treated femurs when compared to the shams. Histological sections did show increased cortical thickness and new bone formation in the DBM and OP-1 groups, with the OP-1 group appearing slightly thicker. Despite the histological changes seen, the results indicate that there is no significant improvement in mechanical strength during the early stages of healing regardless of treatment.

Evaluation of short-term healing following sustained delivery of osteoinductive agents in a rat femur drill defect model.

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Evaluation of short-term healing following sustained delivery of osteoinductive agents in a rat femur drill defect model.