Lactoferrin promotes bone growth

We have demonstrated bovine or human lactoferrin to be an anabolic factor in skeletal tissue. In vitro, lactoferrin stimulates the proliferation of bone forming cells, osteoblasts, and cartilage cells at physiological concentrations (above 0.1 microg/ml). The magnitude of this effect exceeds that observed in response to other skeletal growth factors such as IGF-1 and TGFbeta. DNA synthesis is also stimulated in a bone organ culture system likely reflecting the proliferation of cells of the osteoblast lineage. Lactoferrin is also a potent osteoblast survival factor. In TUNEL and DNA fragmentation assays, lactoferrin decreased apoptosis, induced by serum withdrawal, by up to 70%. In addition, lactoferrin has powerful effects on bone resorbing cells, osteoclasts, decreasing osteoclast development at concentrations > 1 microg/ml in a murine bone marrow culture system. However, lactoferrin did not alter bone resorption in calvarial organ culture, suggesting that it does not influence mature osteoclast function. In vivo, local injection of lactoferrin in adult mice resulted in increased calvarial bone growth, with significant increases in bone area and dynamic histomorphometric indices of bone formation after only 5 injections. Taken together, these data demonstrate that the naturally-occurring glycoprotein lactoferrin is anabolic to bone in vivo, an effect which is consequent upon its potent proliferative and anti-apoptotic actions in osteoblasts, and its ability to inhibit osteoclastogenesis. Lactoferrin may therefore have a physiological role in bone growth, and a potential therapeutic role in osteoporosis.     

Dexamethasone inhibits bone resorption by indirectly inducing apoptosis of the bone-resorbing osteoclasts via the action of osteoblastic cells

Although glucocorticoids (GCs) are physiologically essentialfor bone metabolism, it is generally accepted that high dosesof GCs cause bone loss through a combination of decreased boneformation and increased bone resorption. However, the actionof GCs on mature osteoclasts remains contradictory. In thisstudy, we have examined the effect of GCs on osteoclasticbone-resorbing activity and osteoclast apoptosis, by using twodifferent cell types, rabbit unfractionated bone cells andhighly enriched mature osteoclasts (>95% of purity).Dexamethasone (Dex, 10^-10–10^-7 M) inhibited resorption pit formation on a dentine slice by the unfractionated bone cells in a dose- and time-dependent manner.However, Dex had no effect on the bone-resorbing activity of the isolated mature osteoclasts. When the isolated osteoclastswere co-cultured with rabbit osteoblastic cells, the osteoclastic bone resorption decreased in response to Dex,dependent on the number of osteoblastic cells. Like the effecton the bone resorption, Dex induced osteoclast apoptosis in cultures of the unfractionated bone cells, whereas it did not promote the apoptosis of the isolated osteoclasts. An inhibitorof caspases, Z-Asp-CH2-DCB attenuated both the inhibitory effecton osteoclastic bone resorption and the stimulatory effect onthe osteoclast apoptosis. In addition, the osteoblastic cellswere required for the osteoclast apoptosis induced by Dex. These findings indicate that the main target cells of GCs arenon-osteoclastic cells such as osteoblasts and that GCsindirectly inhibit bone resorption by inducing apoptosis ofthe mature osteoclasts through the action of non-osteoclasticcells. This study expands our knowledge about the multifunctional roles of GCs in bone metabolism.     

VEGF and bone cell signalling: an essential vessel for communication?

Vascular endothelial growth factor (VEGF) is an endothelial cell survival factor and is required for effective coupling of angiogenesis and osteogenesis. Although central to bone homeostasis, repair and the pathobiology that affect these processes, the precise mechanisms coupling endothelial cell function within bone formation and remodelling remain unclarified. This review will (i) focus on the potential directionality of VEGF signalling in adult bone by identifying the predominant source of VEGF within the bone microenvironment, (ii) will summarize current VEGF receptor expression studies by bone cells and (iii) will provide evidence for a role for VEGF signalling during postnatal repair and osteoporosis. A means of understanding the directionality of VEGF signalling in adult bone would allow us to most effectively target angiogenic pathways in diseases characterized by changes in bone remodelling rates and enhance bone repair when compromised. Copyright © 2012 John Wiley & Sons, Ltd.     

microRNAs在骨形成中的作用——运动调控骨代谢的新机制

microRNAs(miRNAs)是一类具有组织或发育阶段特异性的小分子、非编码单链RNA,通过转录后与靶基因特定序列结合来发挥其调控作用. 作为骨中的最重要的两种重要细胞--成骨细胞和破骨细胞,其代谢平衡与骨形成密切相关.研究发现,miRNAs在调节成骨细胞和破骨细胞分化及功能发挥上具有重要作用,并且运动训练可通过调节miRNAs进而调控骨细胞分化. 一般来说,适宜强度运动训练可上调某些miRNAs表达来促进成骨细胞或破骨细胞分化及功能;当失重或过量运动时,则会产生抑制作用. 本文就miRNAs调控干细胞向成骨细胞和破骨细胞分化及功能发挥的分子生物学机制以及运动训练调节与骨代谢相关miRNAs表达的研究进展进行综述.     

Role of active and latent transforming growth factor β in bone formation

At first reading the statement “TGFβ stimulates bone formation but inhibits mineralization” may appear to be an oxymoron. However, the bone formation process can take weeks to months to complete, and the unique properties of TGFβ allow this factor to be stored in bone matrix in a latent form, ready to be activated and inactivated at key, pivotal stages in this long process. TGFβ may act to trigger the cascade of events that ultimately leads to new bone formation. However, once this process is initiated, TGFβ must then be inactivated or removed because if present in the later stages of bone formation, mineralization will be inhibited. The unique properties of TGFβ and its role in bone remodeling are the subject of this review. © 1994 Wiley-Liss, Inc.     

Mechanisms by which cells of the osteoblast lineage control osteoclast formation and activity

The cells of bone are of two lineages, the osteoblasts arising from pluripotential mesenchymal cells and osteoclasts from hemopoietic precursors of the monocyte-macrophage series. Resorption of bone by the multinucleate osteoclast requires the generation of new osteoclastsw and their activation. Many hormones and cytokines are able to promote bone resorption by influencing these processes, but they achieve this without acting directly on osteoclastws. Most evidence indicates that their actions are mediated by cells of the osteoblast lineage. Evidence for hormone-and cytokine-induced activation of osteoclasts requiring the mediation of osteoblasts comes from studies of rsorption by isolated osteoclasts. However, consistent evidence for a spiceific “activating factor” is lacking, and the argument is presented that the isolated osteoclast resorption assays have not been shown convincingly to be assays of osteoclast activation. The view is presented that osteoblast-mediated osteoclast activation is the result of several events in the microenvironment without necessarily requiring the existence of a spicific, essential osteoclast activator. On the other hand, a specific promoter of osteoclast differentiation does seem likely to be a product of cells of the stromal/osteoblast series. Evidence in facour of this comes from studies of osteoclast generation in co-cultures of osteoblast/stromal cells with hemopoietic cells. Conflicting view, maintaining that osteoclasts can develop from hemooietic cells without stromal intervention, might be explaind by varying criteria used in identification of osteoclasts. Osteoblastic and osteoclastic renewal, and the interactions of these lineages, are central to the process of bone remodeling.     

Defence of bipedalism

The long-unresolved and much publicized puzzle of how human ancestors could have ventured upon habitual bipedalism without making themselves highly vulnerable to predation derives from a misunderstanding of the principles upon which predator-prey relations work. Erect stature, regardless of locomotion proficiency, in fact enhances passive, and not simply active, defence against predators. This was the necessary condition, the security ‘cover’, for selection for the elaboration of bipedal behavior. As illustration, I analyse the defence systems ofPan troglodytes and the hunting techniques of their predators, known and potential, in order to hypothesize the defence impact of bipedal selection on the former; the relevance of human experience with felid predators, in particular, is also then explored. Despite known major differences in the late Miocene mammalian predator guild, the predator-prey framework is likely to have been much the same as to-day, making the findings applicable to the situation of proto-hominids. Once it is accepted selection pressure for bipedalism was originally focused on posture and not locomotion, the mystery of its emergence disappears.