The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

The JAK/STAT signaling pathway: from bench to clinic.

Loss of estrogens or androgens increases the rate of bone remodeling by removing restraining effects on osteoblastogenesis and osteoclastogenesis, and also causes a focal imbalance between resorption and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, androgens, as well as estrogens, maintain cancellous bone mass and integrity, regardless of age or sex. Although androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs), can exert these effects, their relative contribution remains uncertain. Recent studies suggest that androgen action on cancellous bone depends on (local) aromatization of androgens into estrogens. However, at least in rodents, androgen action on cancellous bone can be directly mediated via AR activation, even in the absence of ERs. Androgens also increase cortical bone size via stimulation of both longitudinal and radial growth. First, androgens, like estrogens, have a biphasic effect on endochondral bone formation: at the start of puberty, sex steroids stimulate endochondral bone formation, whereas they induce epiphyseal closure at the end of puberty. Androgen action on the growth plate is, however, clearly mediated via aromatization in estrogens and interaction with ERalpha. Androgens increase radial growth, whereas estrogens decrease periosteal bone formation. This effect of androgens may be important because bone strength in males seems to be determined by relatively higher periosteal bone formation and, therefore, greater bone dimensions, relative to muscle mass at older age. Experiments in mice again suggest that both the AR and ERalpha pathways are involved in androgen action on radial bone growth. ERbeta may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males. In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and expansion of cortical bone. Such androgen action on bone is mediated by the AR and ERalpha.

https://www.hormonebalance.org/images/documents/Androgens%20and%20Bone%20Clin%20Endo%2004%20Vander.pdf

Androgens and bone

The Janus kinase (Jak) family is one of ten recognized families of non-receptor tyrosine kinases. Mammals have four members of this family, Jak1, Jak2, Jak3 and Tyrosine kinase 2 (Tyk2). Birds, fish and insects also have Jaks. Each protein has a kinase domain and a catalytically inactive pseudo-kinase domain, and they each bind cytokine receptors through amino-terminal FERM (Band-4.1, ezrin, radixin, moesin) domains. Upon binding of cytokines to their receptors, Jaks are activated and phosphorylate the receptors, creating docking sites for signaling molecules, especially members of the signal transducer and activator of transcription (Stat) family. Mutations of the Drosophila Jak (Hopscotch) have revealed developmental defects, and constitutive activation of Jaks in flies and humans is associated with leukemia-like syndromes. Through the generation of Jak-deficient cell lines and gene-targeted mice, the essential, nonredundant functions of Jaks in cytokine signaling have been established. Importantly, deficiency of Jak3 is the basis of human autosomal recessive severe combined immunodeficiency (SCID); accordingly, a selective Jak3 inhibitor has been developed, forming a new class of immunosuppressive drugs.

/pdf/the-janus-kinases-jaks-137rzx2o0e.pdf

The Janus kinases (Jaks)

The growth plate is the final target organ for longitudinal growth and results from chondrocyte proliferation and differentiation. During the first year of life, longitudinal growth rates are high, followed by a decade of modest longitudinal growth. The age at onset of puberty and the growth rate during the pubertal growth spurt (which occurs under the influence of estrogens and GH) contribute to sex difference in final height between boys and girls. At the end of puberty, growth plates fuse, thereby ceasing longitudinal growth. It has been recognized that receptors for many hormones such as estrogen, GH, and glucocorticoids are present in or on growth plate chondrocytes, suggesting that these hormones may influence processes in the growth plate directly. Moreover, many growth factors, i.e., IGF-I, Indian hedgehog, PTHrP, fibroblast growth factors, bone morphogenetic proteins, and vascular endothelial growth factor, are now considered as crucial regulators of chondrocyte proliferation and differentiation. In this review, we present an update on the present perception of growth plate function and the regulation of chondrocyte proliferation and differentiation by systemic and local regulators of which most are now related to human growth disorders.

/pdf/systemic-and-local-regulation-of-the-growth-plate-1vvm4bgnzn.pdf

Systemic and Local Regulation of the Growth Plate

Androgen receptor (AR) is a member of the steroid and nuclear receptor superfamily,1 which is composed of over 100 members and continues to grow. Among this large family of proteins, only five vertebrate steroid receptors—estrogen, progesterone, androgen, glucocorticoid, and mineralocorticoid receptors—are known. Two subtypes of estrogen receptor have been identified, estrogen receptor α and estrogen receptor β.2 Like other steroid receptors, AR is a soluble protein that functions as an intracellular transcriptional factor. AR function is regulated by the binding of androgens, which initiates sequential conformational changes of the receptor that affect receptor–protein interactions and receptor–DNA interactions.

AR-regulated gene expression is responsible for male sexual differentiation and male pubertal changes. AR ligands are widely used in a variety of clinical applications (i.e., agonists are employed for hypogonadism, while antagonists are used for prostate cancer therapy). Fang et al.3 recently summarized a large number of chemicals that bind to the AR. The current review focuses on well-characterized AR ligands that bind to the AR with high affinity and integrates discussion regarding the biology, metabolism, and structure-activity relationships for therapeutic and emerging classes of AR ligands. The known AR ligands can be classified as steroidal or nonsteroidal based on their structure or as agonist or antagonist based on their ability to activate or inhibit transcription of AR target genes. Synthetic AR ligands were first developed by modifying the steroidal structure of endogenous androgens. The structure–activity relationship of these steroidal AR ligands is well documented4-6 and will only be briefly summarized in this review. However, low oral bio-availability, poor pharmacokinetic properties, and side effects have limited the use of many steroidal AR ligands. Until recently, it was considered impossible to separate the androgenic and anabolic effects of AR ligands due to their reliance on a single AR. However, newly discovered nonsteroidal AR ligands may provide a new strategy to achieve tissue selectivity, as is possible with estrogen receptor ligands. Novel nonsteroidal pharmacophores are summarized in this review with discussion of the emerging structure–activity relationships and examples of their tissue selectivity included.7

1.1. Physiologic Roles and Clinical Application of Androgens
AR is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver, and central nervous system (CNS), with the highest expression level observed in the prostate, adrenal gland, and epididymis as determined by real-time polymerase chain reaction (PCR).8 AR can be activated by the binding of endogenous androgens, including testosterone and 5α-dihydrotestosterone (5α-DHT). Physiologically, functional AR is responsible for male sexual differentiation in utero and for male pubertal changes. In adult males, androgen is mainly responsible for maintaining libido, spermato-genesis, muscle mass and strength, bone mineral density, and erythropoisis.7,9 The actions of androgen in the reproductive tissues, including prostate, seminal vesicle, testis, and accessory structures, are known as the androgenic effects, while the nitrogen-retaining effects of androgen in muscle and bone are known as the anabolic effects.

Numerous and varied site mutations in AR have been identified (The Androgen Receptor Gene Mutations Database World Wide Web Server, http://www.androgendb.mcgill.ca/). The majority of these mutations are associated with diseases, like Androgen Insensitivity Syndrome and prostate cancer. The androgen withdrawal syndrome observed in prostate cancer therapy also appeared to be related to certain AR mutations, such as T877A and W741C mutations, which convert some AR antagonists into agonists (see more discussion in section 3.1.1). Besides the site mutations documented, AR gene polymorphism has also been identified, particularly, the poly-Q (CAG)n at exon I. The polymorphic (CAG)10–35 triplet repeat sequence, starting from codon 58, codes for polyglutamine. The length of the repeat is inversely correlated with the transactivation activity of AR. The correlation between the length of the CAG repeat and disease stage was recently reviewed by Oettel.10

Classically, testosterone is used to treat male hypogonadism, Klinefelter's syndrome, anemia secondary to chronic renal failure, aplastic anemia, protein wasting diseases associated with cancer, burns, traumas,acquiredimmunodeficiencysyndrome(AIDS), etc., short stature, breast cancer (as an anti-estrogen), and hereditary angioedema.7 Recently, hormone replacement therapy in aging males has also been proposed to improve body composition, bone and cartilage metabolism, and certain domains of brain function and even decrease cardiovascular risk.10

/pdf/chemistry-and-structural-biology-of-androgen-receptor-25v3szten5.pdf

Chemistry and structural biology of androgen receptor

In previous studies we established that human bone and human osteoblast-like cells (hOB cells) cultured from bone express 5alpha-reductase (5alpha-R) activity, as demonstrated by the conversion of testosterone and androstenedione to their corresponding 5alpha-reduced metabolites, 5alpha-dihydrotestosterone (DHT) and 5alpha-androstanedione Two 5alpha-R isozymes (types 1 and 2) have been identified in various tissues As their nature in bone is unknown, we investigated which isozymes were expressed in first passage hOB cells cultured from bone specimens obtained from six donors (five women and one man) For comparison, 5alpha-reductase isozyme expression in genital skin fibroblasts cultured from foreskin of three males was determined Pharmacological and biochemical studies using selective inhibitors of the 5alpha-R isozymes were performed, and gene expression was assessed by RT-PCR In hOB cells, LY191704, a potent nonsteroidal selective inhibitor of 5alpha-R type 1, and the 4-azasteroid 17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one (a dual inhibitor of 5alpha-R types 1 and 2) inhibited 5alpha-R activity with a 50% inhibitory concentration (IC(50)) of approximately 4 nM Finasteride, a selective inhibitor of 5alpha-R type 2, blocked 5alpha-R activity with an IC(50) of approximately 60 nM The IC(50) of progesterone, a physiological substrate for 5alpha-R, was approximately 200 nM In genital skin fibroblasts, LY191704 inhibited 5alpha-R with an IC(50) of more than 5000 nM, whereas finasteride and 17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one effectively inhibited 5alpha-R with IC(50) of approximately 4 nM Experiments to determine 5alpha-reductase activity in homogenates of hOB cells as a function of pH showed very low activity at pH 55, but a broad shoulder of activity from pH 60-90, which was not inhibited by finasteride, but was nearly completely blocked by LY191704 RT-PCR revealed that 5alpha-R type 1 and 2 mRNAs were expressed in both bone and genital skin fibroblasts Based on our pharmacological and biochemical studies, it appears that 5alpha-R activity in hOB cells is catalyzed predominantly by the type 1 rather than the type 2 isozyme This expression pattern is in contrast to that in genital skin fibroblasts, where the activity of the type 2 isozyme prevails As in most androgen target tissues DHT is biologically more active as an androgen than testosterone, DHT is formed in bone by 5alpha-R type 1 action from circulating testosterone, and bone cells also express the androgen receptor, local DHT production may play a physiological role in human bone homeostasis

Human Osteoblast-Like Cells Express Predominantly Steroid 5α-Reductase Type 1

Notch signalling is an evolutionarily conserved cell interaction mechanism, the role of which in controlling cell fate choices has been studied extensively. Recent studies in both vertebrates and invertebrates revealed additional functions of Notch in proliferation and apoptotic events. We provide evidence for an essential role of the Notch signalling pathway during morphogenetic cell movements required for the formation of the foregut-associated proventriculus organ in the Drosophila embryo. We demonstrate that the activation of the Notch receptor occurs in two rows of boundary cells in the proventriculus primordium. The boundary cells delimit a population of foregut epithelial cells that invaginate into the endodermal midgut layer during proventriculus morphogenesis. Notch receptor activation requires the expression of its ligand Delta in the invaginating cells and apical Notch receptor localisation in the boundary cells. We further show that the movement of the proventricular cells is dependent on the short stop gene that encodes the Drosophila plectin homolog of vertebrates and is a cytoskeletal linker protein of the spectraplakin superfamily. short stop is transcriptionally activated in response to the Notch signalling pathway in boundary cells and we demonstrate that the localisation of the Notch receptor and Notch signalling activity depend on short stop activity. Our results provide a novel link between the Notch signalling pathway and cytoskeletal reorganisation controlling cell movement during the development of foregut-associated organs.

/pdf/cell-movements-controlled-by-the-notch-signalling-cascade-2tmh0tbb30.pdf

Cell movements controlled by the Notch signalling cascade during foregut development in Drosophila.

Cooperation of JAK/STAT and Notch signaling in the Drosophila foregut.

Distribution of 17β-hydroxysteroid dehydrogenases in human osteoblast-like cells

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Human Osteoblast-Like Cells Express Predominantly Steroid 5α-Reductase Type 1

Cell movements controlled by the Notch signalling cascade during foregut development in Drosophila.

Cooperation of JAK/STAT and Notch signaling in the Drosophila foregut.

Distribution of 17β-hydroxysteroid dehydrogenases in human osteoblast-like cells