Can inhibiting SOCS help you increase in height?

Recently, Hakker has been making some news about SOCS.  SOCS stands for suppressor of cytokine signaling.  Suppressors are more effective than stimulators because suppressors don't usually have to worry about negative feedback mechanisms.  Can SOCS or parts of the pathway help increase height?

A novel role for suppressor of cytokine signaling 3 in cartilage destruction via induction of chondrocyte desensitization toward insulin-like growth factor.

"chondrocyte desensitization toward its main anabolic factor, insulin-like growth factor 1 (IGF-1) [exists] [we want chondrocytes to be as sensitive to IGF-1 as possible as IGF-1 likely plays a role in peak chondrocyte hypertrophy thus helping you grow taller].
IGF-1 desensitization of patellar chondrocytes was studied in zymosan-induced arthritis. IGF-1 desensitization was induced in patellar cartilage explants or the H4 chondrocyte cell line, exposed to interleukin-1alpha (IL-1alpha)[so an interleukin inhibitor like many anti-oxidants will help you increase height].  The role of SOCS-3{LSJL upregulates SOCS3} in IGF-1 signaling was elucidated by adenoviral overexpression.
Exposure of murine articular cartilage to IL-1 caused a significant decrease in IGF-1-induced PG synthesis. This effect also occurred in inducible nitric oxide synthase-knockout mice, revealing the involvement of a secondary IL-1-induced factor other than nitric oxide. IL-1 significantly up-regulated SOCS-3 transcription and protein synthesis in H4 chondrocytes. IL-18 was unable to induce SOCS-3 expression and failed to induce chondrocyte IGF-1 desensitization. arthritic knee joints revealed high expression of SOCS-3 in chondrocytes. SOCS-3 inhibits IGF-1-mediated cell signaling, since IRS-1 phosphorylation{LSJL downregulates IRS1} was reduced."

This study indicates that SOCS may actually reduce height by decreasing IGF-1 sensitivity in chondrocytes.

"insulin-like growth factor 1 (IGF-1), [controls]  cartilage homeostasis by inducing the production of extracellular matrix components, such as aggrecan[more proteoglycan synthesis likely helps make you taller]. Cartilage damage results from the disparity between anabolic and catabolic factors. Essential catabolic factors, such as IL-1 and tumor necrosis factor α (TNFα), are well-known inhibitors of chondrocyte PG synthesis, with IL-1 being more potent than TNFα"

"IGF-1 can stimulate PG synthesis to superoptimal levels in chondrocytes"<-thus making the growth plate area larger and you eventually taller

But it's still possible that SOCS may help make you taller by a non-IGF-1 related mechanism.  For example, SOCS may inhibit FGFR3 which inhibits height growth.

Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling.

"Fibroblast growth factor receptor (FGFR) signaling is transduced by the mitogen-activated protein kinase (MAPK) cascade and the signal transducers and activators of transcription (STATs). Suppressors of cytokine signaling (SOCS) proteins are expressed in response to cytokine-inducible stimulation of STAT phosphorylation, acting in a negative-feedback mechanism to hinder the activities of these receptors. activation of FGFR in chondrocytes induces the expression of SOCS1 and SOCS3 mRNA, and that these proteins are constitutively associated with FGFR3[FGFR3 induces SOCS3 so SOCS3 may play a role in FGFR3's height reducing effects]. Transfection of cells with FGFR3-GFP and SOCS1-CFP revealed their colocalization, clustered prominently in the perinuclear cytosolic part of the cell. The effect of the interaction between FGFR3 and SOCS1 on receptor activity was investigated in a chondrocytic cell line overexpressing SOCS1. In these cells, STAT1 phosphorylation is repressed, MAPK phosphorylation is elevated and prolonged, and FGFR3 downregulation is attenuated[So SOCS1 reduces FGFR3 downregulation which is bad because we want FGFR3 to be downregulated as much as possible.]. Expression of osteopontin (OPN), which is directly upregulated by FGF in chondrocytes, was stimulated by lower levels of FGF in cells expressing SOCS1 compared with parental cells. Blocking of MAPK phosphorylation by PD98059 decreased OPN expression in both cell types, but this decrease was more marked in cells expressing SOCS1. SOCS1 and SOCS3 proteins [interact with the] FGFR3 signaling pathway."

So both SOCS3 and SOCS1 have effects that are bad for height growth.  SOCS3 in relation to IGF-1 and SOCS1 in relation to FGFR3.  Since LSJL upregulates SOCS3 we may want to use exogenous means to upregulate IGF1 to compensate.

"SOCS1 inhibits cytokine signaling by interaction of its SH2 domain with phosphorylated Tyr1007 of JAK2, whereas SOCS3 binds to activated cytokine receptors through its SH2 domain and inhibits JAK2 phosphorylation"

"in the presence of SOCS1, FGFR3 is re-routed to recycling endosomes from its natural course of downregulation and degradation."<-we want FGFR3 to be downregulated and degraded.

"Stimulation of FGFR3 enhances two major pathways: the STAT pathway, which inhibits chondrocyte proliferation[so we want to inhibit the STAT pathway]; and the MAPK cascade, which contributes to matrix synthesis and inhibition of chondrocyte differentiation[inhibition of chondrocyte differentiation may be good as it may give the chondrocytes more time to secrete matrix and hypertrophy thus each individual chondrocyte contributes more to adult height].  Overexpression of SOCS1 in RCS cells attenuates FGF-induced STAT1 phosphorylation, similar to the activity of STAT in cytokine receptors; however, in parallel, it elevates the MAPK pathway by extending the duration of its signal."

Muramyl dipeptide inhibits SOCS1 but it does not appear to be available by normal means.  There is a drug called Mifamurtide which is a derivative of muramyl dipeptide.

Muramyldipeptide augments the actions of lipopolysaccharide in mice by stimulating macrophages to produce pro-IL-1β and by down-regulation of the suppressor of cytokine signaling 1 (SOCS1).

"Muramyldipeptide (MDP), the minimum essential structure responsible for the immuno-adjuvant activity of peptidoglycan, is recognized by intracellular nuclear-binding oligomerization domain 2 (NOD2). Muramyldipeptide enhances the activities of lipopolysaccharide (LPS).  Intravenously injected MDP augments LPS-induced hypothermia in wild-type mice, but not in mice deficient in interleukin (IL)-1α/β and/or tumor-necrosis factor (TNF)-α. Muramyldipeptide also: (i) increased pro-IL-1β in tissues, but did not increase IL-1β in serum (since caspase-1 was not activated by MDP); (ii) downregulated the expression of suppressor of cytokine signaling 1 (SOCS1; a negative-feedback regulator of LPS-induced signaling); and (iii) augmented the LPS-induced production of TNF-α, IL-12 p40, and interferon (IFN)-γ[the inhibitions of SOCS1 expression being the important factor]. macrophages were involved in these effects of MDP[macrophages are white blood cells]. Two different mechanisms may underlie the augmenting effect of MDP: namely, stimulation of pro-IL-1β production by, and down-regulation of SOCS1 in, macrophages."

SOCS2 is more important than SOCS3 in height reduction.

SOCS proteins: negative regulators of cytokine signaling.

"Cytokines regulate the growth and differentiation of cells by binding to cell-surface receptors and activating intracellular signal transduction cascades such as the JAK-STAT pathway. Cytokine signaling is negatively regulated with respect to both magnitude and duration, and it is now clear that the suppressor of cytokine signaling (SOCS) family of proteins (SOCS1-SOCS7 and CIS) contributes significantly to this process. Transcripts encoding CIS, SOCS1, SOCS2, and SOCS3 are upregulated in response to cytokine stimulation[so these four proteins are likely involved in the negative feedback to cytokine stimulation], and the corresponding SOCS proteins inhibit cytokine-induced signaling pathways. SOCS proteins therefore form part of a classical negative feedback circuit. SOCS family members modulate signaling by several mechanisms, which include inactivation of the Janus kinases (JAKs), blocking access of the signal transducers and activators of transcription (STATs) to receptor binding sites, and ubiquitination of signaling proteins and their subsequent targeting to the proteasome. Socs2(-/-) mice are 30%-40% larger than wild-type mice, demonstrating that SOCS2 is a critical regulator of postnatal growth[thus SOCS2 inhibition might help increase height]."

1st column is inhibited.  2nd Column is associated.  Bold is upregulated in LSJL.  Italics is downregulated in LSJL.

"

CIS	IL-2; IL-3 ; prolactin; Epo; IGF-1; GH	Epo receptor; IL-3 receptor; GH receptor; IL-2 receptor; PCKθ
SOCS1	IL-2; IL-3; IL-4; IL-6; GH; prolactin; Epo; LIF; IFN-γ; IFN-α; OSM; TSLP; Tpo; IGF-1	JAK1; JAK2; JAK3; Grb2; Vav; FGF receptor; PYK2; GH receptor; Kit receptor; Flt3 receptor; IGF-1 receptor
SOCS2	GH; IL-6; LIF; IGF-1; prolactin	IGF-1 receptor; prolactin receptor; GH receptor
SOCS3	IL-2; IL-3; IL-4; IL-6; GH; prolactin; Epo; LIF; IFN-γ; IFN-α; CNTF; leptin; OSM; IGF-1; insulin	Lck; FGF receptor; PYK2; GH receptor; Epo receptor; leptin receptor; gp130; IGF-1 receptor

"<-so SOCS2 lowers IGF-1 and GH sensitivity

"This weight increase[from SOCS2 knockout] is not attributable to excess fat, but rather to a significant increase in visceral organ weight, carcass weight, long bone length and body length"<-SOCS2 inhibition increases height.

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis.

"Suppressor of Cytokine Signaling-2 (SOCS2) is a negative regulator of growth hormone (GH) signaling and bone growth via inhibition of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway.  SOCS2(-/-) mice, [which have an overgrowth phenotype], [have] normal systemic insulin-like growth factor 1 (IGF-1) levels[so you can grow taller by reducing SOCS2 levels].  SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes after GH challenge. Gain- and loss-of-function studies indicated that GH-stimulated chondrocyte STATs-1, -3, and -5 phosphorylation was increased in SOCS2(-/-) chondrocytes but not in cells overexpressing SOCS2. Increased chondrocyte STAT signaling in the absence of SOCS2 [may] explain the observed GH stimulation of longitudinal growth of cultured SOCS2(-/-) embryonic metatarsals and the proliferation of chondrocytes within. bone growth rates, growth plate widths, and chondrocyte proliferation were all increased in SOCS2(-/-) 6-week-old mice as was the number of phosphorylated STAT-5-positive hypertrophic chondrocytes."

So inhibiting SOCS1, 2, and 3(and possibly others) can help increase height during development. Since cytokines also play a role in cellular differentiation it is also possible that inhibiting these molecules may help after adulthood by allowing easier stem cell differentiation into chondrocytes by a method such as LSJL.

"GH has no effect on prenatal growth, whereas GHR null mice present with impaired growth from approximately 2 weeks after birth. Systemic IGF-1 deficiency retards both pre- and postnatal growth, and IGF-1 receptor null mice, exhibiting a more severe growth deficiency, die shortly after birth."

"STAT-1, -3, and -5 are activated by GH, and the JAK/STAT-5b pathway is pivotal for growth promotion where inactivating mutations or elimination in mice of STAT-5b, but not STAT-5a, results in reduced growth. In humans, mutations of GHR or STAT-5b that result in the inhibition of STAT-5b signaling without alteration of STAT-1 and -3, MAPK or ERK signaling results in severe IGF-1 deficiency and short stature."

"Epiphyseal chondrocytes express SOCS2, and growth plates from SOCS2 null mice are enlarged with wider proliferative and hypertrophic zones."

"the SOCS2 overgrowth phenotype is dependent on STAT-5b downstream signaling events only and that uninhibited GH signaling through STATs-1 and -3 does not contribute to the SOCS2 overgrowth phenotype."

"reduced STAT activation in the presence of SOCS2 prevents GH from promoting growth of metatarsals maintained in culture. GH does have the potential to locally regulate bone growth, but this ability is tempered by the chondrocyte expression levels of SOCS2."<-So maybe people with high GH but don't have gigantism express high levels of SOCS2.

"IGF-1 had no effect on STAT phosphorylation."

Inflammation and linear bone growth: the inhibitory role of SOCS2 on GH/IGF-1 signaling.

"Linear bone growth is widely recognized to be adversely affected in children with chronic kidney disease (CKD) and other chronic inflammatory disorders. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is anabolic to the skeleton and inflammatory cytokines[inflammatory cytokines like IL-6 could also be anabolic] compromise bone growth through a number of different mechanisms, which include interference with the systemic as well as the tissue-level GH/IGF-1 axis. there are an increasing number of reports of the persistence of poor growth in a substantial proportion of patients receiving rhGH and/or drugs that block cytokine action.  Suppressor of cytokine signaling 2 (SOCS2) expression is increased in inflammatory conditions including CKD, and is a recognized inhibitor of GH signaling."

So inflammatory actions also induce anabolic responses so you only want to inhibit SOCS2.

"Reduced bone growth is more severe in the double ghr/igf-1r mutants than in either ghr and igf-1 null mice alone and it is likely therefore that GH and IGF-1 have both independent and common functions "

"The global inactivation of ghr ghrhr, Igf-1, Igf-1r and Irs-1 in mice all result in growth retardation"

"chondrocyte-produced IGF-1 as a regulator of growth was demonstrated in mice with a targeted deletion Igf-1 in chondrocytes. These mice had reduced body length, a 40% reduction in cartilage IGF-1 expression but normal serum IGF-1 levels"<-so chondrocyte produced IGF-1 is the main determinant of height not systematic so injecting IGF-1 should not increase height but injecting compounds that increase endogenous production of IGF-1 will increase height.

"tamoxifen-inducible, cartilage-specific Igfr knockout mice showed significant growth retardation with a disorganized growth plate with reduced chondrocyte proliferation and collagen type II expression"

SOCS inhibits JAK2 and STAT phosphorylation.

"CKD patients have been reported to have elevated circulating levels of ILs-1β, 6, 12, 15, and 18 and TNFα, and uremic mice have higher IL-6 serum levels"

"skeletal muscle has also been shown to contribute to circulating plasma IL-6 levels during hemodialysis"

"Direct inhibitory effects of IL-1β and TNFα on linear bone growth of metatarsals maintained in organ culture have been reported, whereas IL-6 does not retard metatarsal growth or reduce collagen II and X and proteoglycan production by chondrocytes"

STAT5 null mice show growth retardation.

STAT1 KO mice are normal size.

"Socs2 −/− overgrowth phenotype is dependent on increased GH signaling via STAT5, and not STATs 1 and 3. "

"IL-1β and TNFα both increase the expression of SOCS2 by growth plate chondrocytes"

Epiphyseal growth plate growth hormone receptor signaling is decreased in chronic kidney disease-related growth retardation.

"Linear growth retardation in children with chronic kidney disease (CKD) has been ascribed to insensitivity to growth hormone. This resistance state has been attributed to impaired growth hormone signaling through the JAK2/STAT5 pathway in liver and skeletal muscle leading to reduced insulin-like growth factor-I (IGF-I). Here we determine whether systemic and growth plate alterations in growth hormone signaling contribute to CKD-induced linear growth retardation using partially nephrectomized and pair-fed control 20-day-old rats. Serum growth hormone did not change in rats with CKD, yet serum IGF-I levels were decreased and growth retarded. The tibial growth plate hypertrophic zone was wider and vascularization at the primary ossification center was reduced in CKD. This was associated with a decrease in growth plate vascular endothelial growth factor (VEGF) mRNA and immunostainable VEGF and IGF-I levels. Growth plate growth hormone receptor and STAT5 protein levels were unchanged, while JAK2 was reduced. Despite comparable growth hormone and growth hormone receptor levels in CKD and control rats, relative STAT5 phosphorylation was significantly depressed in CKD. Of note, the mRNA of SOCS2, an inhibitor of growth hormone signaling, was increased. Thus, linear growth impairment in CKD can in part be explained by impaired long bone growth plate growth hormone receptor signaling through the JAK2/STAT5 pathway, an abnormality that may be caused by an increase in SOCS2 expression."

"There were no changes in proliferative zone width between the groups, whereas a significant increase in the width of the hypertrophic zone was seen" CKD increased Col10 mRNA.

"IGFBP2 inhibits IGF-mediated proliferation and matrix synthesis in growth plate chondrocytes"

Increased bone mass, altered trabecular architecture and modified growth plate organization in the growing skeleton of SOCS2 deficient mice

"Suppressor of Cytokine Signaling-2 (SOCS2) negatively regulates the signal transduction of several cytokines. Socs2-/- mice show increased longitudinal skeletal growth associated with deregulated GH/IGF-1 signaling. The present study examined the role of SOCS2 in endochondral ossification and trabecular and cortical bone formation, and investigated whether pro-inflammatory cytokines associated with pediatric chronic inflammatory disorders mediate their effects through SOCS2.
7-week-old Socs2-/- mice were heavier (27%) and longer (6%) than wild-type mice. Socs2-/- tibiae were longer (8%) and broader (18%) than that of wild-type mice, and the Socs2-/- mice had wider growth plates (24%) with wider proliferative and hypertrophic zones (10% and 14% respectively).
Socs2-/- mice showed increased total cross-sectional bone area (16%), coupled to increased total tissue area (17%) compared to tibia from wild-type mice.
Socs2-/- mice showed increased percent bone volume (101%), trabecular number (82%) and trabecular thickness (11%), with associated decreases in trabecular separation (19%). TNFα exposure to growth plate chondrocytes for 48h increased SOCS2 protein expression. Growth of metatarsals from 1-day-old Socs2-/- and Socs2+/+ mice, as well as expression of Aggrecan, Collagen Type II
and Collagen Type X, were inhibited by TNFα, with no effect of genotype.
Physiological levels of SOCS2 negatively regulate bone formation and endochondral growth.  Pro-inflammatory cytokines mediate their inhibitory effects on longitudinal bone growth through a mechanism that is independent of SOCS2."

"SOCS2 may block access of STAT5 to the activated GH receptor"

"SOCS2 may bind to the IGF-I receptor and inhibit IGF-I induced STAT3 activation"

"Primary chondrocytes derived from both fetal (E14-E18) and neonatal (1 and 9-day-old) cartilage were found to express Socs2 mRNA, whereas terminally-differentiated ATDC5 cells showed decreased SOCS2 protein levels compared to ATDC5 cells in the chondrogenic phase"

"wild-type and Socs2-/- mice showed comparable metatarsal lengths at E19 and 1 day of age and their growth curves did not significantly diverge until 4 weeks of age."

"Socs2 null mice have been shown to exhibit several features of deregulated GH/IGF-I signaling, including collagen accumulation in the dermis, affected production of major urinary protein, and increased local production of IGF-I in several organs including the heart, lungs and spleen"