The bone remodelling cycle Kenkre, J S; Bassett, Jhd
Annals of clinical biochemistry,
05/2018, Letnik:
55, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The bone remodelling cycle replaces old and damaged bone and is a highly regulated, lifelong process essential for preserving bone integrity and maintaining mineral homeostasis. During the bone ...remodelling cycle, osteoclastic resorption is tightly coupled to osteoblastic bone formation. The remodelling cycle occurs within the basic multicellular unit and comprises five co-ordinated steps; activation, resorption, reversal, formation and termination. These steps occur simultaneously but asynchronously at multiple different locations within the skeleton. Study of rare human bone disease and animal models have helped to elucidate the cellular and molecular mechanisms that regulate the bone remodelling cycle. The key signalling pathways controlling osteoclastic bone resorption and osteoblastic bone formation are receptor activator of nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin and canonical Wnt signalling. Cytokines, growth factors and prostaglandins act as paracrine regulators of the cycle, whereas endocrine regulators include parathyroid hormone, vitamin D, calcitonin, growth hormone, glucocorticoids, sex hormones, and thyroid hormone. Disruption of the bone remodelling cycle and any resulting imbalance between bone resorption and formation leads to metabolic bone disease, most commonly osteoporosis. The advances in understanding the cellular and molecular mechanisms underlying bone remodelling have also provided targets for pharmacological interventions which include antiresorptive and anabolic therapies. This review will describe the remodelling process and its regulation, discuss osteoporosis and summarize the commonest pharmacological interventions used in its management.
Studies in genetically modified mice have highlighted the importance of the hypothalamic-pituitary-thyroid (HPT) axis during skeletal development and the maintenance of adult bone. Recently, the ...conventional view that skeletal responses to abnormal thyroid status result solely from altered T3 action in bone has been complicated by studies proposing TSH as a negative regulator of bone turnover. Although skeletal consequences of thyrotoxicosis may result from thyroid hormone excess or TSH deficiency, the two alternatives are not necessarily mutually exclusive and cannot easily be differentiated because the HPT axis maintains them in a physiological reciprocal relationship. By contrast, situations in which this inverse relationship is disrupted have the potential to resolve the roles of T3 and TSH in the skeleton. We discuss these situations and the relative importance of T3 and TSH in skeletal homeostasis.
Triiodothyronine (T3) classically regulates gene expression by binding to high-affinity thyroid hormone receptors (TR) that recognize specific response elements in the promoters of T3-target genes ...and activate or repress transcription in response to hormone. However, a number of thyroid hormone effects occur rapidly and are unaffected by inhibitors of transcription and translation, suggesting that thyroid hormones may also mediate non-genomic actions. Such actions have been described in many tissues and cell types, including brown adipose tissue, the heart and pituitary. The site of non-genomic hormone action has been localized to the plasma membrane, cytoplasm and cellular organelles. These non-genomic actions include the regulation of ion channels, oxidative phosphorylation and mitochondrial gene transcription and involve the generation of intracellular secondary messengers and induction of Ca
2+
I, cyclic AMP or protein kinase signalling cascades. These observations have been interpreted to imply the presence of a specific, membrane associated, TR isoform or an unrelated high affinity membrane receptor for thyroid hormone. The recent identification of a progestin membrane receptor and the sub cellular targeted nuclear receptor isoforms ER46, mtRXR, mtPPAR, p28 and p46, has highlighted the potential importance of non-genomic actions of steroid hormones. Here we compare these recently identified receptors with the genomic, non-genomic and mitochondrial actions of thyroid hormones and consider their implications.
Thyroid hormone (T
3) is essential for the normal development of endochondral and intramembranous bone and plays an important role in the linear growth and maintenance of bone mass. Childhood T
3 ...deficiency results in retardation of skeletal development and growth arrest, whereas T
3 excess leads to accelerated growth and bone formation. In adult thyrotoxicosis, there is increased bone remodelling, characterized by an imbalance between bone resorption and formation, which results in net bone loss and an increased risk for posteoporotic fracture. These clinical observations demonstrate the importance of T
3 in skeletal development and metabolism. Nevertheless, the molecular mechanisms of T
3 action in bone are poorly understood. Here, we provide an overview of T
3 regulation of chondrocytes, osteoblasts and osteoclasts, and the actions of thyroid hormone receptor (TR) isoforms in skeletal development. The possible roles of T
3 and TRs in nuclear receptor crosstalk, prereceptor ligand metabolism, heparan sulfate proteoglycan synthesis and angiogenesis are also considered.
Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the ...monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using
and
cell-based techniques, and
models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.
Childhood hypothyroidism delays ossification and bone mineralization, whereas adult thyrotoxicosis causes osteoporosis. To determine how effects of thyroid hormone (T3) during development manifest in ...adult bone, we characterized TRalpha1(+/m)beta(+/-) mice, which express a mutant T3 receptor (TR) alpha1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TRalpha1(+/m)beta(+/-) mice had osteosclerosis with increased bone mineralization even though juveniles had delayed ossification. This phenotype was partially normalized by transient T3 treatment of juveniles and fully reversed in compound TRalpha1(+/m)beta(-/-) mutant mice due to 10-fold elevated hormone levels that allow the mutant TRalpha1 to bind T3. By contrast, deletion of TRbeta in TRalpha1(+/+)beta(-/ -) mice, which causes a 3-fold increase of hormone levels, led to osteoporosis in adults but advanced ossification in juveniles. T3-target gene analysis revealed skeletal hypothyroidism in TRalpha1(m/+)beta(+/-) mice, thyrotoxicosis in TRalpha1(+/+)beta(-/-) mice, and euthyroidism in TRalpha1(+/)beta(-/-) double mutants. Thus, TRalpha1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization.
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