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Physiological Reviews Oct 2018Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and... (Review)
Review
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.
Topics: Animals; Bone Morphogenetic Proteins; Gene Expression Regulation; Humans; Osteogenesis; Signal Transduction; Skeleton
PubMed: 30156494
DOI: 10.1152/physrev.00028.2017 -
The Cochrane Database of Systematic... Oct 2016Osteogenesis imperfecta is caused by a genetic defect resulting in an abnormal type I collagen bone matrix which typically results in multiple fractures with little or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Osteogenesis imperfecta is caused by a genetic defect resulting in an abnormal type I collagen bone matrix which typically results in multiple fractures with little or no trauma. Bisphosphonates are used in an attempt to increase bone mineral density and reduce these fractures in people with osteogenesis imperfecta. This is an update of a previously published Cochrane Review.
OBJECTIVES
To assess the effectiveness and safety of bisphosphonates in increasing bone mineral density, reducing fractures and improving clinical function in people with osteogenesis imperfecta.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of journals and conference proceedings. We additionally searched PubMed and major conference proceedings.Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Register: 28 April 2016.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials comparing bisphosphonates to placebo, no treatment, or comparator interventions in all types of osteogenesis imperfecta.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data and assessed the risk of bias of the included trials.
MAIN RESULTS
Fourteen trials (819 participants) were included. Overall, the trials were mainly at a low risk of bias, although selective reporting was an issue in several of the trials. Data for oral bisphosphonates versus placebo could not be aggregated; a statistically significant difference favouring oral bisphosphonates in fracture risk reduction and number of fractures was noted in two trials. No differences were reported in the remaining three trials which commented on fracture incidence. Five trials reported data for spine bone mineral density; all found statistically significant increased lumbar spine density z scores for at least one time point studied. For intravenous bisphosphonates versus placebo, aggregated data from two trials showed no statistically significant difference for the number of participants with at least one fracture, risk ratio 0.56 (95% confidence interval 0.30 to 1.06). In the remaining trial no statistically significant difference was noted in fracture incidence. For spine bone mineral density, no statistically significant difference was noted in the aggregated data from two trials, mean difference 9.96 (95% confidence interval -2.51 to 22.43). In the remaining trial a statistically significant difference in mean per cent change in spine bone mineral density z score favoured intravenous bisphosphonates at six and 12 months. Data describing growth, bone pain, and functional outcomes after oral or intravenous bisphosphonate therapy, or both, as compared to placebo were incomplete among all studies, but do not show consistent improvements in these outcomes. Two studies compared different doses of bisphosphonates. No differences were found between doses when bone mineral density, fractures, and height or length z score were assessed. One trial compared oral versus intravenous bisphosphonates and found no differences in primary outcomes. Two studies compared the intravenous bisphosphonates zoledronic acid and pamidronate. There were no significant differences in primary outcome. However, the studies were at odds as to the relative benefit of zoledronic acid over pamidronate for lumbosacral bone mineral density at 12 months.
AUTHORS' CONCLUSIONS
Bisphophonates are commonly prescribed to individuals with osteogenesis imperfecta. Current evidence, albeit limited, demonstrates oral or intravenous bisphosphonates increase bone mineral density in children and adults with this condition. These were not shown to be different in their ability to increase bone mineral density. It is unclear whether oral or intravenous bisphosphonate treatment consistently decreases fractures, though multiple studies report this independently and no studies report an increased fracture rate with treatment. The studies included here do not show bisphosphonates conclusively improve clinical status (reduce pain; improve growth and functional mobility) in people with osteogenesis imperfecta. Given their current widespread and expected continued use, the optimal method, duration of therapy and long-term safety of bisphosphonate therapy require further investigation. In addition, attention should be given to long-term fracture reduction and improvement in quality of life indicators.
Topics: Administration, Oral; Bone Density; Bone Density Conservation Agents; Diphosphonates; Fractures, Bone; Humans; Injections, Intravenous; Osteogenesis Imperfecta; Randomized Controlled Trials as Topic
PubMed: 27760454
DOI: 10.1002/14651858.CD005088.pub4 -
Journal of Korean Neurosurgical Society May 2022Pediatric spine has growth potential with incomplete ossification, and also unique biomechanics which have important implications for trauma patients. This article...
Pediatric spine has growth potential with incomplete ossification, and also unique biomechanics which have important implications for trauma patients. This article intends to review various aspects of pediatric spine trauma including epidemiology, anatomy and biomechanics, and clinically relevant details of each type of injury based on the location and mechanism of injury. With the appropriate but not superfluous treatment, pediatric spine trauma patients can have better chance of recovery. Therefore, as a spine surgeon, understanding the general concept for each injury subtype together with the debate and progress in the field is inevitable.
PubMed: 35462522
DOI: 10.3340/jkns.2021.0282 -
International Journal of Molecular... Nov 2021The accumulation of glycosaminoglycans (GAGs) in bone and cartilage leads to progressive damage in cartilage that, in turn, reduces bone growth by the destruction of the... (Review)
Review
The accumulation of glycosaminoglycans (GAGs) in bone and cartilage leads to progressive damage in cartilage that, in turn, reduces bone growth by the destruction of the growth plate, incomplete ossification, and growth imbalance. The mechanisms of pathophysiology related to bone metabolism in mucopolysaccharidoses (MPS) include impaired chondrocyte function and the failure of endochondral ossification, which leads to the release of inflammatory cytokines via the activation of Toll-like receptors by GAGs. Although improvements in the daily living of patients with MPS have been achieved with enzyme replacement, treatment for the bone disorder is limited. There is an increasing need to identify biomarkers related to bone and cartilage to evaluate the progressive status and to monitor the treatment of MPS. Recently, new analysis methods, such as proteomic analysis, have identified new biomarkers in MPS. This review summarizes advances in clinical bone metabolism and bone biomarkers.
Topics: Biomarkers; Bone Remodeling; Bone and Bones; Cytokines; Humans; Mucopolysaccharidoses; Proteomics
PubMed: 34884458
DOI: 10.3390/ijms222312651 -
Proceedings of the National Academy of... Feb 2021Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a...
Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a pancartilaginous program to form cartilaginous skeletal primordia, and also embrace a growth-plate program to drive skeletal growth or an articular program to build permanent joint cartilage. Various forms of cartilage malformation and degeneration diseases afflict humans, but underlying mechanisms are still incompletely understood and treatment options suboptimal. The transcription factor SOX9 is required for embryonic chondrogenesis, but its postnatal roles remain unclear, despite evidence that it is down-regulated in osteoarthritis and heterozygously inactivated in campomelic dysplasia, a severe skeletal dysplasia characterized postnatally by small stature and kyphoscoliosis. Using conditional knockout mice and high-throughput sequencing assays, we show here that SOX9 is required postnatally to prevent growth-plate closure and preosteoarthritic deterioration of articular cartilage. Its deficiency prompts growth-plate chondrocytes at all stages to swiftly reach a terminal/dedifferentiated stage marked by expression of chondrocyte-specific () and progenitor-specific ( and ) genes. Up-regulation of osteogenic genes (, , and ) and overt osteoblastogenesis quickly ensue. SOX9 deficiency does not perturb the articular program, except in load-bearing regions, where it also provokes chondrocyte-to-osteoblast conversion via a progenitor stage. Pathway analyses support roles for SOX9 in controlling TGFβ and BMP signaling activities during this cell lineage transition. Altogether, these findings deepen our current understanding of the cellular and molecular mechanisms that specifically ensure lifelong growth-plate and articular cartilage vigor by identifying osteogenic plasticity of growth-plate and articular chondrocytes and a SOX9-countered chondrocyte dedifferentiation/osteoblast redifferentiation process.
Topics: Animals; Cartilage, Articular; Cell Differentiation; Cell Lineage; Chondrocytes; Chondrogenesis; Growth Plate; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts; Osteogenesis; SOX9 Transcription Factor
PubMed: 33597301
DOI: 10.1073/pnas.2019152118 -
Balkan Medical Journal Sep 2017Morphologically congenital sensorineural hearing loss can be investigated under two categories. The majority of congenital hearing loss causes (80%) are membranous...
Morphologically congenital sensorineural hearing loss can be investigated under two categories. The majority of congenital hearing loss causes (80%) are membranous malformations. Here, the pathology involves inner ear hair cells. There is no gross bony abnormality and, therefore, in these cases high-resolution computerized tomography and magnetic resonance imaging of the temporal bone reveal normal findings. The remaining 20% have various malformations involving the bony labyrinth and, therefore, can be radiologically demonstrated by computerized tomography and magnetic resonance imaging. The latter group involves surgical challenges as well as problems in decision-making. Some cases may be managed by a hearing aid, others need cochlear implantation, and some cases are candidates for an auditory brainstem implantation (ABI). During cochlear implantation, there may be facial nerve abnormalities, cerebrospinal fluid leakage, electrode misplacement or difficulty in finding the cochlea itself. During surgery for inner ear malformations, the surgeon must be ready to modify the surgical approach or choose special electrodes for surgery. In the present review article, inner ear malformations are classified according to the differences observed in the cochlea. Hearing and language outcomes after various implantation methods are closely related to the status of the cochlear nerve, and a practical classification of the cochlear nerve deficiency is also provided.
Topics: Classification; Cochlea; Cochlear Nerve; Ear, Inner; Hearing Loss, Sensorineural; Humans; Osteogenesis; Temporal Bone; Tomography, X-Ray Computed
PubMed: 28840850
DOI: 10.4274/balkanmedj.2017.0367 -
Nature Communications Jul 2023Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using...
Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using carefully validated antibodies to analyze senescent cells at single-cell resolution. We use multiple criteria to identify senescent mesenchymal cells that are growth-arrested and resistant to apoptosis. These p16 + Ki67-BCL-2+ cells are highly enriched for senescence-associated secretory phenotype and DNA damage markers, are strongly associated with age, and their percentages are increased in late osteoblasts/osteocytes and CD24 osteolineage cells. Moreover, both late osteoblasts/osteocytes and CD24 osteolineage cells are robustly cleared by genetic and pharmacologic senolytic therapies in aged mice. Following isolation, CD24+ skeletal cells exhibit growth arrest, senescence-associated β-galactosidase positivity, and impaired osteogenesis in vitro. These studies thus provide an approach using multiplexed protein profiling to define senescent mesenchymal cells in vivo and identify specific skeletal cell populations cleared by senolytics.
Topics: Mice; Animals; Cellular Senescence; Senotherapeutics; Aging; Osteoblasts; Skeleton
PubMed: 37524694
DOI: 10.1038/s41467-023-40393-9 -
Theranostics 2021Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences...
Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer. Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes . Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA. Implantation of SCP28 tumor cells leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations. Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.
Topics: Animals; Bone Density; Bone Neoplasms; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Exosomes; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Osteoclasts; Osteogenesis; RNA-Binding Proteins; Tumor Microenvironment
PubMed: 33391543
DOI: 10.7150/thno.45351