(2019) Repair of long-bone pseudoarthrosis with autologous bone marrow mononuclear cells combined with allogenic bone graft Long-bone Pseudoarthrosis Allogenic grafts supplementation with autologous BM-MNCs Fernandez-Bances et al. remodelling is key to incorporating new and effective treatment methods for bone disease. gene [86]. Age-related reduction in bone healing ability is usually caused by an increasing imbalance of bone formation and resorption. Current osteoporosis treatments include pharmacological brokers which attempt to slow down bone resorption, including bisphosphonates and/or estrogenics, or increase bone formation via parathyroid hormone peptides [85,87]. Combined with these treatments, early screenings for those most at risk combined with the lowering of risk factors due to way of life, such as tobacco smoking, alcohol intake and poor diet, is recommended. Furthermore, novel treatments based on inhibitors of bone resorption or stimulators of bone formation can target bone resorption/formation independently, effectively uncoupling these processes and leading to more efficient and effective treatment [87]. The long term use of these medications has been linked to impairments in bone microarchitecture, as well as a rebound effect following the discontinuation of drug use, increasing the risk of multiple fractures [88,89]. Therefore, the challenge remains to find safe, effective treatments which minimize secondary risks. Cathepsin-K (CatK), expressed in osteoclasts, is usually a cysteine protease important to bone resorption, particularly the breakdown of bone collagen. Notably, a rare hereditary disorder known as pycnodysostosis can occur when the gene is usually mutated, causing cathepsin-K deficiency and manifesting as the high bone density phenotype [90]. The CatK inhibitor odanacatib showed potential as a therapeutic agent to reduce bone resorption; however, following a link to increased risk of stroke in clinical trials, production of the drug was discontinued as of 2016 [88,90]. A tendency of MSCs in the body to favour an adipocyte lineage over osteoblast increases with age [2,91]. This could be caused by the downregulation of osteogenic genesand and [92]. Also important to note is the age-related decrease in efficacy of Wnt signalling, leading to reduced repression of genes, each encoding a lipid-modified glycoprotein [147]. These WNT proteins interact with frizzled (FZD) cell surface receptors to activate intracellular pathways and regulate development across ST 101(ZSET1446) organisms. The key regulatory step is the inhibition of the AXIN1 complex, responsible for degradation of -catenin, the downstream effector protein of the Wnt pathway [148]. It has also been suggested that WNT proteins act as paracrine factors through secretion in extracellular vesicles including exosomes [12]. The complex Wnt pathway is usually believed to be important for osteogenic differentiation, as loss-of-function mutations in low-density lipoprotein receptor-related protein 5 (LRP5a co-receptor of WNT) were found Rabbit Polyclonal to ANGPTL7 to cause osteoporosis-pseudoglioma syndrome, while gain-of-function mutations in LRP5 caused osteosclerosis [146,149]. These conditions are characterised by abnormally low, or high bone density respectively. The relationship between the regulation of the Wnt pathway and osteoblast differentiation could show relevant to researching new methods of bone treatment. ST 101(ZSET1446) The promotion of Wnt signalling in mice by the introduction of the L-WNT3A protein motivated autograft healing potential [105]. WNT antagonists such as Dickkopf-related protein 1 and sclerostin could also be inhibited to encourage osteoblast differentiation [147]. Sclerostin, encoded by the gene, and Dickkopf-related protein 1, encoded by the gene, can both inhibit the Wnt signalling pathway through binding to the LRP5/6 co-receptors [150,151]. Exosomes released from neighbouring cells can transfer genetic information such as miRNAs, as well as proteins such as WNTs and thereby regulate cell signalling, influencing the cell fate of precursor cells [12,152]. Approximately one third of the human genome is regulated by microRNAs (miRNAs). These non-coding RNAs, of which over 2000 have been described in humans, each regulate the expression of hundreds of genes by binding mRNA prior to translation and encouraging the degradation of the mRNA. The development of miRNAs as therapeutic treatments involves the production of a mimic in cases of diseases caused by miRNA dysfunction, or an inhibitor in the cases of diseases with abnormally high levels of miRNAs [153]. Several miRNAs have already been linked to osteogenic differentiation. Apart from regulating differentiation in precursor cells, miRNAs can ST 101(ZSET1446) also stabilize a pluripotent state after cell dedifferentiation into induced pluripotent stem cells.
