Receptor oligomerization and beyond: a case study in bone morphogenetic proteins

Heinecke, Kai; Seher, Axel; Schmitz, W.; Mueller, Thomas D.; Sebald, Walter; Nickel, J. Curtis

doi:10.1186/1741-7007-7-59

Cited by 120 publications

(163 citation statements)

References 59 publications

(77 reference statements)

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“…When BMPR2 is reduced or absent, increased BMP utilization of ACVR2A/B occurs at the expense of activin signaling. Although unexpected, this finding is supported by the fact that, in general, the affinity of BMPs for ACVR2A/B is in the same range as the affinity for BMPR2 (Allendorph et al, 2006;Berasi et al, 2011;Daly and Hearn, 2006;Greenwald et al, 2003;Greenwald et al, 2004;Heinecke et al, 2009;Hu et al, 2010;Isaacs et al, 2010;Kirsch et al, 2000;Knaus and Sebald, 2001;Koncarevic et al, 2010;Rosenzweig et al, 1995;Sako et al, 2010;Sengle et al, 2008), and BMPs also possess a flexible mode of receptor complex assembly, which might enhance their ability to compete with activins that have only a single mode of complex assembly (Hinck, 2012). Because bone cells have abundant type 1 BMP receptors (ALK2, ALK3 and ALK6, BioGPS Database), preformed receptor complexes might also be biased toward BMP binding.…”

Section: Discussionmentioning

confidence: 50%

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Lowery

Intini

Gamer

et al. 2015

Journal of Cell Science

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Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFb signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFb signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level competition between BMPs and activins and where utilization of ACVR2A and ACVR2B by BMPs comes at the expense of activins. As BMP and activin pathway modulation are of current therapeutic interest, our findings provide important mechanistic insight into the relationship between these pathways in human health.

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Section: Discussionmentioning

confidence: 50%

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Lowery

Intini

Gamer

et al. 2015

Journal of Cell Science

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“…BMPR-1B (BMP receptor IB), BMPR-II, and activin receptor (ActR) type IIB have higher affinities for the GDF-5 ligand [83,84,85]. Upon GDF-5 binding, the receptors are phosphorylated to activate the downstream Smad pathway.…”

Section: Gdf-5: a Member Of The Bmp Familymentioning

confidence: 99%

Growth and Differentiation Factor-5 Contributes to the Structural and Functional Maintenance of the Intervertebral Disc

Feng

Liu

Yang

et al. 2015

Cell Physiol Biochem

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Intervertebral disc degeneration (IDD) is a widely recognized contributor to low back pain (LBP). The Prevention or reversal of IDD is a potential treatment for LBP. Unfortunately, current treatments for IDD are aimed at relieving symptoms rather than regenerating disc structure or function. Recently, the injection of growth factors and mesenchymal stem cell (MSC) transplantation have been shown to be promising biological therapies for IDD. Growth factors stimulate the proliferation of and matrix synthesis by intervertebral disc (IVD) cells, leading to the regeneration of degenerative discs. Growth factors, hypoxia and co-culture with nucleus pulposus (NP) cells induce MSCs to differentiate toward an NP-like phenotype, which can increase the number of functional cells in the IVD or enhance the function of endogenous disc cells to facilitate IVD regeneration. Therefore, the emerging roles of growth factors in IVD regeneration have piqued the interest of researchers. Growth factors including transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), insulin-like growth factor-1 (IGF-1) and growth and differentiation factor-5 (GDF-5), among others, have been demonstrated to enhance anabolism in IVD cells and to induce NP-like differentiation of MSCs. However, the injection of TGF, IGF and FGF into human IVDs may induce unwanted blood vessel ingrowth, which accelerates the process of IDD, the injection of GDF-5 may not have the same effect. This finding suggests that GDF-5 is a preferable growth factor for use in IDD treatment compared with TGF, IGF and FGF. The GDF-5 gene is one of the few growth factor genes that have been found to be associated with IDD thus far; moreover, the GDF-5 gene defects lead to collagen and proteoglycan abnormalities in discs in mice, suggesting that GDF-5 contributes to the structural and functional maintenance of the IVD. This review is focused on the functions of GDF-5 in the IVD and on the association between GDF-5 and a genetic predisposition to IDD. The effects of GDF-5 on IVD regeneration and on MSC differentiation are also discussed. GDF-5 plays a crucial role in the pathogenesis of IDD and is a promising therapeutic agent for IDD. Additionally, stem cell transplantation has been shown to be a promising biological therapy for IDD.

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“…BMPs are known to stimulate both osteogenesis and adipogenesis, depending upon the microenvironment. 50,51 The complexities inherent in BMP2-related signaling pathways may be related to the observation that clinical responses to rBMP2 are often unpredictable. 52 Given these issues, a method that enables controlled and localized delivery of BMP2, utilizing lower doses that do not evoke harmful side effects, would have a major impact on treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of the Regenerative Potential of Anorganic Bovine Bone Graft Utilizing a Polyglutamate-Modified BMP2 Peptide with Improved Binding to Calcium-Containing Materials

Bain

Bonvallet

Abou‐Arraj

et al. 2015

Tissue Engineering Part A

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Autogenous bone is the gold standard material for bone grafting in craniofacial and orthopedic regenerative medicine. However, due to complications associated with harvesting donor bone, clinicians often use commercial graft materials that may lose their osteoinductivity due to processing. This study was aimed to functionalize one of these materials, anorganic bovine bone (ABB), with osteoinductive peptides to enhance regenerative capacity. Two peptides known to induce osteoblastic differentiation of mesenchymal stem cells were evaluated: (1) DGEA, an amino acid motif within collagen I and (2) a biomimetic peptide derived from bone morphogenic protein 2 (BMP2pep). To achieve directed coupling of the peptides to the graft surface, the peptides were engineered with a heptaglutamate domain (E7), which confers specific binding to calcium moieties within bone mineral. Peptides with the E7 domain exhibited greater anchoring to ABB than unmodified peptides, and E7 peptides were retained on ABB for at least 8 weeks in vivo. To assess the osteoinductive potential of the peptide-conjugated ABB, ectopic bone formation was evaluated utilizing a rat subcutaneous pouch model. ABB conjugated with full-length recombinant BMP2 (rBMP2) was also implanted as a model for current clinical treatments utilizing rBMP2 passively adsorbed to carriers. These studies showed that E7BMP2pep/ABB samples induced more new bone formation than all other peptides, and an equivalent amount of new bone as compared with rBMP2/ABB. A mandibular defect model was also used to examine intrabony healing of peptide-conjugated ABB. Bone healing was monitored at varying time points by positron emission tomography imaging with 18 F-NaF, and it was found that the E7BMP2pep/ABB group had greater bone metabolic activity than all other groups, including rBMP2/ABB. Importantly, animals implanted with rBMP2/ABB exhibited complications, including inflammation and formation of cataract-like lesions in the eye, whereas no side effects were observed with E7BMP2pep/ABB. Furthermore, histological analysis of the tissues revealed that grafts with rBMP2, but not E7BMP2pep, induced formation of adipose tissue in the defect area. Collectively, these results suggest that E7-modified BMP2-mimetic peptides may enhance the regenerative potential of commercial graft materials without the deleterious effects or high costs associated with rBMP2 treatments.

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Receptor oligomerization and beyond: a case study in bone morphogenetic proteins

Cited by 120 publications

References 59 publications

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Growth and Differentiation Factor-5 Contributes to the Structural and Functional Maintenance of the Intervertebral Disc

Enhancement of the Regenerative Potential of Anorganic Bovine Bone Graft Utilizing a Polyglutamate-Modified BMP2 Peptide with Improved Binding to Calcium-Containing Materials

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