A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone

Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) play important roles in bone metabolism. Smad ubiquitination regulatory factors (Smurfs) regulate TGF-β/BMP signaling via ubiquitination, resulting in degradation of signaling molecules to prevent excessive activation of TGF-β/BMP signaling. Though Smurf2 has been shown to negatively regulate TGF-β/Smad signaling, its involvement in BMP/Smad signaling in bone metabolism has not been thoroughly investigated. In the present study, we sought to evaluate the role of Smurf2 in BMP/Smad signaling in bone metabolism. Absorbable collagen sponges containing 3 μg of recombinant human BMP2 (rhBMP2) were implanted in the dorsal muscle pouches of wild type (WT) and Smurf2−/− mice. The rhBMP2-induced ectopic bone in Smurf2−/− mice showed greater bone mass, higher mineral apposition and bone formation rates, and greater osteoblast numbers than the ectopic bone in WT mice. In WT mice, the ectopic bone consisted of a thin discontinuous outer cortical shell and scant inner trabecular bone. In contrast, in Smurf2−/− mice, the induced bone consisted of a thick, continuous outer cortical shell and abundant inner trabecular bone. Additionally, rhBMP2-stimulated bone marrow stromal cells (BMSCs) from Smurf2−/− mice showed increased osteogenic differentiation. Smurf2 induced the ubiquitination of Smad1/5. BMP/Smad signaling was enhanced in Smurf2−/− BMSCs stimulated with rhBMP2, and the inhibition of BMP/Smad signaling suppressed osteogenic differentiation of these BMSCs. These findings demonstrate that Smurf2 negatively regulates BMP/Smad signaling, thereby identifying a new regulatory mechanism in bone metabolism.

Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes

Bone strength is determined by its dense cortical shell, generated by unknown mechanisms. Here we use the Dmp1Cre:Socs3f/f mouse, with delayed cortical bone consolidation, to characterise cortical maturation and identify control signals. We show that cortical maturation requires a reduction in cortical porosity, and a transition from low to high density bone, which continues even after cortical shape is established. Both processes were delayed in Dmp1Cre:Socs3f/f mice. SOCS3 (suppressor of cytokine signalling 3) inhibits signalling by leptin, G-CSF, and IL-6 family cytokines (gp130). In Dmp1Cre:Socs3f/f bone, STAT3 phosphorylation was prolonged in response to gp130-signalling cytokines, but not G-CSF or leptin. Deletion of gp130 in Dmp1Cre:Socs3f/f mice suppressed STAT3 phosphorylation in osteocytes and osteoclastic resorption within cortical bone, leading to rescue of the corticalisation defect, and restoration of compromised bone strength. We conclude that cortical bone development includes both pore closure and accumulation of high density bone, and that these processes require suppression of gp130-STAT3 signalling in osteocytes.

Effect of vertebral degeneration on the instability of spine

Insufficient exploration of the dependence between diseases of degenerative bones and the range of motion (ROM) during torsion, flexion and lateral bending limits further understanding about the lumbar biomechanics and treating of the lumbar related dysfunction. The objective of this study was to determine the effect of vertebral degradation on the instability of spine 2 motion L2–L4 segments during torsion, flexion and lateral bending by the finite element method (FEM). Three different 3D FE models comprising the healthy state and the degradation of trabecular bone and cortical bone were developed. Nonlinear numerical analyses of lumbar spine stability discovered that osteoporotic degradation can lead to critical segmental ROM and intervertebral shearing values, which results in the loss of spine stability for the case of flexion loading. Instability is caused by microscopic changes in the thickness of cortical shell. This analysis of the intervertebral shearing and ROM may be further used to diagnose such translation abnormalities like hypomobility or hypermobility.

Geometrical Properties of Skeletal Structures of Radiolarian Genus Didymocyrtis

This paper discusses the geometrical properties of a radiolarian skeletal structure, namely, that of genus Didymocyrtis. We characterized the evolution of skeletal structures and analyzed the structures using geometry. We defined two ratios in order to quantify the geometrical properties of Didymocyrtis and verified that the two ratios changed with their phylogenic evolution. We also used the 3D skeletal data of a specimen of species D. tetrathalamus, which was obtained through micro X-ray CT. The cortical shell obtained in the 3D data was projected onto a spherical surface, and we determined the centers of the pores. Our analysis revealed that the number of pores is approximately 200 and their distribution is not regular. We also determined that the column-like parts of the skeleton, which connect the inner and upper parts of the specimen, do not lie on a plane and their intervals are not equal.

Vascularized Bone-Mimetic Hydrogel Constructs by 3D Bioprinting to Promote Osteogenesis and Angiogenesis

Bone is a highly vascularized tissue with a unique and complex structure. Long bone consists of a peripheral cortical shell containing a network of channels for vascular penetration and an inner highly vascularized bone marrow space. Bioprinting is a powerful tool to enable rapid and precise spatial patterning of cells and biomaterials. Here we developed a two-step digital light processing technique to fabricate a bone-mimetic 3D hydrogel construct based on octacalcium phosphate (OCP), spheroids of human umbilical vein endothelial cells (HUVEC), and gelatin methacrylate (GelMA) hydrogels. The bone-mimetic 3D hydrogel construct was designed to consist of a peripheral OCP-containing GelMA ring to mimic the cortical shell, and a central GelMA ring containing HUVEC spheroids to mimic the bone marrow space. We further demonstrate that OCP, which is evenly embedded in the GelMA, stimulates the osteoblastic differentiation of mesenchymal stem cells. We refined the design of a spheroid culture device to facilitate the rapid formation of a large number of HUVEC spheroids, which were embedded into different concentrations of GelMA hydrogels. It is shown that the concentration of GelMA modulates the extent of formation of the capillary-like structures originating from the HUVEC spheroids. This cell-loaded hydrogel-based bone construct with a biomimetic dual ring structure can be potentially used for bone tissue engineering.