Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms.

Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 Å and the prodomain-bound BMP9:ALK1 complex at 3.3 Å. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway.

Advances in the molecular regulation of endothelial BMP9 signalling complexes and implications for cardiovascular disease.

Bone morphogenetic protein 9 (BMP9), a member of the transforming growth factor ß (TGFß) superfamily, is a circulating vascular quiescence and endothelial protective factor, accounting for the majority of BMP activities in plasma. BMP9 and BMP10 bind preferentially to the high-affinity type I receptor activin receptor-like kinase 1 on vascular endothelial cells. Recently, many reports have highlighted the important roles of BMP9 in cardiovascular disease, particularly pulmonary arterial hypertension. In vivo, BMP9 activity and specificity are determined by tightly regulated protein-protein recognition with cognate receptors and a co-receptor, and may also be influenced by other proteins present on the endothelial cell surface (such as low-affinity receptors) and in circulation (such as TGFß family ligands competing for the same receptors). In this review, we summarise recent findings on the role and therapeutic potential of BMP9 in cardiovascular disease and review the current understanding of how the extracellular protein-protein interaction milieu could play a role in regulating endothelial BMP9 signalling specificity and activity.

Advanced concepts in knee arthrodesis.

The aim is to describe advanced strategies that can be used to diagnose and treat complications after knee arthrodesis and to describe temporary knee arthrodesis to treat infected knee arthroplasty. Potential difficult complications include nonunited knee arthrodesis, limb length discrepancy after knee arthrodesis, and united but infected knee arthrodesis. If a nonunited knee arthrodesis shows evidence of implant loosening or failure, then bone grafting the nonunion site as well as exchange intramedullary nailing and/or supplemental plate fixation are recommended. If symptomatic limb length discrepancy cannot be satisfactorily treated with a shoe lift, then the patient should undergo tibial lengthening over nail with a monolateral fixator or exchange nailing with a femoral internal lengthening device. If a united knee arthrodesis is infected, the nail must be removed. Then the surgeon has the option of replacing it with a long, antibiotic cement-coated nail. The authors also describe temporary knee arthrodesis for infected knee arthroplasty in patients who have the potential to undergo insertion of a new implant. The procedure has two goals: eradication of infection and stabilization of the knee. A temporary knee fusion can be accomplished by inserting both an antibiotic cement-coated knee fusion nail and a static antibiotic cement-coated spacer. These advanced techniques can be helpful when treating difficult complications after knee arthrodesis and treating cases of infected knee arthroplasty.