Does smoking stunt growth?

Like masturbation and not eating your vegetables(or wheaties), smoking is one of the activities associated with short stature.  Smoking has a little more research behind it in terms of it's growth stunting effects.

Degeneration of intervertebral discs due to smoking: experimental assessment in a rat-smoking model. 

"We have investigated the intervertebral discs of rat-smoking models to demonstrate that smoking is a cause of degenerative intervertebral disc disease. A smoking box was developed for this study. We exposed 8-week-old rats to indirect tobacco smoke inhalation. Each rat was forced to inhale the smoke from one cigarette per hour. The mean blood nicotine level of rodents exposed to cigarette smoke corresponds to about twice that of ordinary human smokers. Histological and immunological studies were then performed to assess the effects of smoking for varying periods of time. After 8 weeks, the chondrocytes in the disordered annulus fibrosus layer tended to grow larger and attain a rounder form than normal chondrocytes. The interleukin-1beta level in the 8-week smoking group was significantly higher than that of the control group. Tobacco smoke inhalation increased local production and release of inflammatory cytokines and resultant decomposition of chondrocyte activity." 

Tobacco increases inflammatory cytokines(like Tumor Necrosis Factor-Alpha and interleukin-1beta) which kill chondrocytes(including growth plate chondrocytes).  Note:  That according to a study listed here it's either hypoxia or necrosis that causes growth plate senescence and not apoptosis.  

"Nicotine, the main ingredient of tobacco, induces a catecholamine stimulus and is said to shrink the peripheral blood vessels."<-since chondrocytes are avascular this might actually be useful for increasing hypoxia to allow for chondrogenesis.

The scientists mentioned that there are several key differences to humans and rats and that humans intervertebral discs may respond differently to cigarette smoking.

Effect of nicotine on spinal disc cells: a cellular mechanism for disc degeneration.

"The most widely accepted explanations for the association between smoking and disc degeneration is malnutrition of spinal disc cells by carboxy-hemoglobin-induced anoxia or vascular disease. Nicotine, a constituent of tobacco smoke, present in most body fluids of smokers is known to have detrimental effects on a variety of tissues. It may also be directly responsible for intervertebral disc (IVD) degeneration by causing cell damage in both the nucleus pulposus and anulus fibrosus. The effect of nicotine 
on IVD cells has not previously been investigated.
Bovine chondrocytic intervertebral disc cells were isolated by sequential digestion of nucleus pulposus and seeded in 2% alginate. The constructs were cultured for 21 days either in growth medium containing freebase nicotine (Sigma) at concentrations found in the serum of smokers (25 nmol/L-300 nmol/L) or in standard nicotine free-medium as controls. Samples were collected at time points 3, 7, 14, and 21 days and a quantitative assay was performed for DNA, glycosaminoglycans (GAG), and hydroxyproline. Samples were also processed for qualitative histologic analysis including immunolocalization of collagen types I and II.
There was both a dose- and time-dependent response to nicotine, with constructs cultured in low-nicotine concentration media demonstrating an early increase in DNA, GAG, and collagen content[can low nicotine levels increase height growth?], while constructs cultured in high nicotine concentration media demonstrated a late decrease in these parameters. At 25 nmol/L dose of nicotine, there was a significant increase (P < 0.05) in the above parameters at day 7 compared with the controls. At higher doses, there was a significant dose-dependent decrease (P < 0.05) in these parameters compared to controls; however, this was only significant at day 14 for the 300 nmol/L group and at day 21 for the 100 nmol/L, 200 nmol/L, and 300 nmol/L groups. Adverse morphologic changes were observed on histology, which included reduced cell proliferation, disrupted cell architecture, disintegration of cells, and extracellular matrix. Immunohistochemistry revealed the presence of type I collagen in the extracellular matrix rather than the normal type II collagen seen in the controls.
Nicotine has an overall detrimental effect on NP disc cells cultured in vitro. There was significant inhibition of cell proliferation and extracellular matrix synthesis."

Interesting that smoking had beneficial effects at small doses(25 nmol/l). Smoking inhibits cellular proliferation and ECM so it's sort of like a reverse Lateral Synovial Joint Loading.

"Nicotine(C10H14N2, 1-methyl-2-(3pyridyl)pyrrolidine) is a naturally occurring plant alkaloid derived from the tobacco plant Nicotiana Tabacum. It is the prototypic agonist for nicotinic receptors such as those found in the central nervous system, autonomic nervous system and neuromuscular junctions. It enters the systemic circulation and diffuses freely through capillaries into extravascular spaces and in its freeform is distributed rapidly to most body tissues including, liver, spleen, muscle, and fat. It crosses the blood–brain barrier freely to have its central nervous system effects. The distribution half-life, which describes the movement of nicotine from the blood and other rapidly perfused tissues, such as the brain, to other body tissues, is approximately 9 minutes, and numerous investigators have confirmed its presence in the body fluids of smokers."<-the plasma levels of nicotine in smokers have ranged to 50 nmol/L(light smokers) to 300 nmol/L. So the beneficial effects of nicotine occur at half the levels of those present in light smokers.

Influence of maternal nicotine exposure on neonatal rat bone: protective effect of ascorbic acid. 

"Limited research in young adults and immature animals suggests a detrimental effect of tobacco on bone during growth. We aimed to determine the adverse effects of maternal nicotine exposure during pregnancy and lactation on neonatal rat bone development, and to determine a protective effect of ascorbic acid. Gravid rats were assigned into three groups: two experimental and one control (group I). In the first experimental group (group II), pregnant rats received 3 mg/kg/d nicotine subcutaneously during pregnancy from 1 to 21 days of gestation and lactation (until postnatal day 21). The second experimental group (group III) received nicotine and ascorbic acid (1 mg/kg body mass/d). Whole body mineral density (BMD), content (BMC), and area (BA) were measured on postnatal day 21. Histopathologic and morphologic findings of the femur were obtained. Maternal nicotine exposure decreased the body weight of the rat at the birth and postnatal day 21. The values of BMD, BA, and BMC of the groups were similar to each other. Width of the epiphyseal plate and the hypertrophic zone were higher in group III but lower in group II than in group I. Number of apoptotic chondrocytes was significantly increased in group II. The length of femur was higher in group I but lower in group II than in group III. Maternal nicotine exposure during gestation and lactation resulted in decreased body weight and bone lengthening. Ascorbic acid supplementation was found to prevent the adverse effects of maternal nicotine exposure on the growth plate." 

Vitamin C is a form of Ascorbic Acid. There is plain ascorbic acid available however:  Ascorbic Acid Powder 1 Pounds.  Not that the Nicotine + Ascorbic Acid group had the highest growth plate width.  Not in the first study mentioned that the chondrocytes eventually attained a rounder form which could account for the growth plate width. 

Influence of maternal nicotine exposure on neonatal rat bone: protective effect of pentoxifylline.

"Limited research in young adults and immature animals suggests a detrimental effect of tobacco on bone during growth. The aim of this study was to determine the adverse effects of maternal nicotine exposure during pregnancy and lactation on neonatal rat bone development, and to determine a protective effect of pentoxifylline (PTX). Gravid rats were assigned into four groups, one control (group I) and three experimental (groups II, III, and IV). In group II, pregnant rats received 3 mg/kg/day nicotine alone, subcutaneously, until 21 days postnatal. In group III, pregnant rats received nicotine (3 mg/kg/day) and PTX (60 mg/kg/day). In group IV, pregnant rats received PTX alone (60 mg/kg/day). Whole body mineral density (BMD), content (BMC), area (BA), and histopathologic and morphologic findings of the femur were determined at 21 days of age. The study revealed that nicotine exposure (group II) decreased birth weight, pregnancy weight gain, and length of femur compared with other groups (P < 0.01). Birth weight was higher in groups III (PTX + nicotine) and IV (PTX) than in group II (nicotine). Body weight at 21 days of age was higher (P = 0.009) in the PTX alone group (group IV) compared with the other groups. BMD was higher (P < 0.001) in the PTX-treated groups (group III and IV) compared with other groups. In addition, there were more apoptotic chondrocytes in the hypertrophic zone of rats exposed to nicotine alone (group II) compared with the other groups (P < 0.001). In conclusion, maternal nicotine exposure resulted in decreased birth weight, pregnancy weight gain, and bone lengthening, and increased apoptosis. Pentoxifylline supplementation was found to prevent the adverse effects of maternal nicotine exposure on BMD and birth weight."

Note Pentoxifylline is an inhibitor of PDEs so like Viagra it could possibly increase height growth.   The PTX treated groups also increased BMD versus controls.

Nicotine acts on growth plate chondrocytes to delay skeletal growth through the alpha7 neuronal nicotinic acetylcholine receptor.

"Among a plethora of cigarette chemicals, nicotine is one of the primary candidate compounds responsible for the cause of smoking-induced delayed skeletal growth. Localization of neuronal nicotinic acetylcholine receptor (nAChR), a specific receptor of nicotine, has been widely detected in non-excitable cells. Therefore, we hypothesized that nicotine affect growth plate chondrocytes directly and specifically through nAChR to delay skeletal growth.
We investigated the effect of nicotine on human growth plate chondrocytes, a major component of endochondral ossification. The chondrocytes were derived from extra human fingers. Nicotine inhibited matrix synthesis and hypertrophic differentiation in human growth plate chondrocytes in suspension culture in a concentration-dependent manner. Both human and murine growth plate chondrocytes expressed alpha7 nAChR, which constitutes functional homopentameric receptors. Methyllycaconitine (MLA), a specific antagonist of alpha7 nAChR, reversed the inhibition of matrix synthesis and functional calcium signal by nicotine in human growth plate chondrocytes in vitro. To study the effect of nicotine on growth plate in vivo, ovulation-controlled pregnant alpha7 nAChR +/- mice were given drinking water with or without nicotine during pregnancy, and skeletal growth of their fetuses was observed. Maternal nicotine exposure resulted in delayed skeletal growth of alpha7 nAChR +/+ fetuses but not in alpha7 nAChR -/- fetuses, implying that skeletal growth retardation by nicotine is specifically mediated via fetal alpha7 nAChR.
These results suggest that nicotine, from cigarette smoking, acts directly on growth plate chondrocytes to decrease matrix synthesis, suppress hypertrophic differentiation via alpha7 nAChR, leading to delayed skeletal growth."

Maybe inhibiting alpha7 nAChR can increase height without the prescence of nicotine.

"Nicotine suppressed Col X expression and enzyme activity of alkaline phosphatase (ALP) in a concentration-dependent manner"<-It also decreased Col2A1 and Ihh.

"Nicotine elicited a transient increase of intra-cellular calcium in a concentration-dependent manner"

So excessive levels of smoking can stunt growth by increasing inflammatory cytokines that kill growth plate chondrocytes.  Small doses of nicotine may actually have height boosting effects by increasing GAGs(like Chondroitin), Collagen, and DNA.  Methyllycaconitine and pentoxifylline may help increase growth regardless of nicotine.  Ascorbic Acid(including Vitamin C) can help prevent cell damage by inflammatory cytokines.

Here's another study that showed a positive effect of nicotine on stem cells at low doses:

[Effects of nicotine on bone marrow stromal cells proliferation and differentiation of chondrocyte in vitro].

"BMSCs was obtained from femoral bone and tibia of New-Zealand albino rabbit. The cells of the 3rd generation were used in study. Different concentration of nicotine (0, 1 x 10(-7), 1 x 10(-6), 1 x 10(-5) M) were added into BMSCs. BMSCs proliferation was analyzed by MTT assay at the 1, 4, 7, 14 days. The expression of collagen type II and aggrecan as the marker genes of cartilaginous differentiation from BMSCs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR).
Microscope showed that BMSCs transformed from round to fusiform shape. The concentration of nicotine in 1 x 10(-7), 1 x 10(-6) M had a significant positive effect on cell proliferation and the expression of type II collagen in a time-dependent manner when supplemented in commonly used induction media (P<0.05). Concentrations of nicotine in 1 x 10(-7) can promote the expression of aggrecan at the 7th day after induction,and in 1 x 10(-5) M may inhibit the expression of type II collagen and aggrecan.
It was implied that local application of nicotine at an appropriate concentration may be a promising approach for enhancing cartilaginous differentiation capacity of BMSCs in cartilage tissue engineering."

So how do we get concentrations of nicotine at 1 X 10(-6) into our blood stream? We'd need to have blood tests done.

Here's a study that shows the positive effects of nicotine on chondrocytes:

Nicotine promotes proliferation and collagen synthesis of chondrocytes isolated from normal human and osteoarthritis patients.

"The aims of the study were to show the direct effect of nicotine with different concentrations (0, 25, 50, and 100 ng/ml) on chondrocytes isolated from normal human and osteoarthritis patients, respectively. Microscopic observation was performed during the culture with an inverted microscope. Methyl thiazolyl tetrazolium (MTT) assay method was adopted to observe the influence of nicotine on the proliferation of chondrocytes, and real-time PCR and ELISA were used to assay the mRNA and protein expression of type II collagen and aggrecan, respectively. We discovered that the OA chondrocytes were similar to fibroblasts in shape and grow slower than normal chondrocytes. The proliferation of the two kinds of chondrocytes was increased in a concentration-dependent manner and in a time-dependent manner (P<0.05). Also, we found that the mRNA level of type II collagen were upregulated under 25-100 ng/ml nicotine doses both in the two kinds of chondrocytes compared with control. The expression of protein levels of type II collagen were synthesized in line with the increase in mRNA. No effect was observed on aggrecan synthesis with any nicotine dose. We concluded that nicotine has the same effect on both chondrocytes, obtained either from osteoarthritis patients or from normal human, and the positive effect of smoking in OA may relate to the alteration in metabolism of chondrocytes."

The other study on nicotine on chondrocytes was on rats whereas this was on humans so that would explain why humans got positive results with higher doses.

50ng/ml was found to be the most beneficial dose on normal chondrocytes with 100ng/ml starting to reduce the effects on COL2A1(Nicotine did not seem to increase Aggrecan levels). However nicotine continued to increase it's benefit on COL2A1 at 100ng/ml with osteoarthritic chondrocytes(Only at 4 days and not at 7 days). Osteoarthritic chondrocytes already have high levels of inflammatory cytokines. If the beneficial effects of nicotine were due to beneficial effects of low levels of inflammatory cytokines, you'd expect nicotine to have no benefit on chondrogenesis in osteoarthritis. This means that nicotines beneficial effect is likely not related to an increase in various cytokines.

"nAChR consisting of a homopentamer of α7 atypically provides gating to calcium ions. Nicotine [evokes] transient calcium fluxes and increased intracellular calcium. From these results, we speculated that changes in the intracellular levels of Ca2 +, following binding of nicotine to its receptor and subsequent activation of voltage-dependent Ca2 + channels, may modulate, at least in part, the effects of nicotine on the proliferation and metabolism of chondrocytes. "<-So Nicotine at low doses may bind to nAChR to increase Ca2+ levels. Calcium may have an equilibrium level explaining why higher doses of Nicotine do not continue to increase Col2A1 levels.

So nicotine alters intracellular calcium signaling.  We should find a way to directly target intracellular calcium signaling to induce mesenchymal chondrogenesis.

Here's a study that shows negative effects of nicotine on chondrogenesis:

Effect of nicotine on chondrogenic differentiation of rat bone marrow mesenchymal stem cells in alginate bead culture.

"Rat BMSCs were capsulated in alginate beads incubated with a chondrogenic differentiation medium and while chondrogenic differentiation of rat BMSCs were cultured for 4 weeks treated with nicotine at concentrations of 25, 50 and 100 μM. The effect of nicotine on BMSCs viability was tested using MTT assay. After chondrogenic differentiation, alginate beads sections were stained for glycosaminoglycan (GAG) with alcian blue and safranin-O. The mRNA expression of chondrogenesis related genes, including collagen type 2 alpha 1 (Col2A1), aggrecan, insulin-like growth factor-1 (IGF-1) were determined by RT-PCR. Nicotine did not affect viability of BMSCs at any indicated concentration. Continuous exposure to nicotine for 4 weeks resulted in significant decrease of the area stained with alcian blue and safranin-O in a concentration-dependent manner compared with the control (P<0.05). After 4 weeks in chondrogenic medium, nicotine dose-dependently decreased the expression of aggrecan, Col2A1 and IGF-1 genes in rat BMSCs chondrogenesis compared with the control (P<0.05). It turned out that nicotine suppresses chondrogenic differentiation potential of BMSCs, leading to a poorly differentiated cartilage."

This study had similar doses as other studies but a longer time frame.  So in addition to small doses you only want to take nicotine for a small period of time, likely under seven days.

Smoking may cause genetic polymorphisms in IGF related proteins.

Smoking, green tea consumption, genetic polymorphisms in the insulin-like growth factors and lung cancer risk.

"IGF-binding protein (IGFBP)-3 could suppress the mitogenic action of IGFs[thus we want less IGFBP-3 if we want to grow taller but IGFBP-3 also inhibits apoptosis]. Tea polyphenols could substantially reduce IGF1 and increase IGFBP3[we should not drink tea if we want to increase height]. Questionnaires were administered to obtain the subjects' characteristics, including smoking habits and green tea consumption from 170 primary lung cancer cases and 340 healthy controls. Genotypes for IGF1, IGF2, and IGFBP3 were identified by polymerase chain reaction."

"ApaI polymorphism (rs680) in the IGF2 gene region of chromosome 11p15 and serum IGF2 concentrations"<-we want this polymorphism.

Nicotine-induced chondrogenic differentiation of human bone marrow stromal cells in vitro.

"The aims of the study were to examine the effects of nicotine (0, 10(-7), 10(-6) and 10(-5) M) on the proliferation and chondrogenic differentiation of BMSCs from three healthy donors in vitro.

BMSCs proliferation was analyzed by CCK8 assay and real-time polymerase chain reaction was used to assay the expression of type II collagen, aggrecan, type I collagen and type X collagen. The proteoglycan content was stained by Alcian blue, and the sulfated glycosaminoglycan (sGAG) content of BMSCs was quantified spectrofluorometrically using dimethylmethylene blue.

The cell viability was not significantly impaired until up to a concentration of 10(-5) M nicotine. Nicotine promoted the proliferation and enhanced the expression of type II collagen at the level up to 10(-6) M (P < 0.05). The expression of aggrecan was reduced at the concentration of 10(-5) M nicotine at day 14 (P < 0.05), and there was no significant difference in aggrecan gene expression at 10(-7) and 10(-6) M nicotine levels compared to control group (n.s.). Also the fibroblastic and hypertrophic gene expressions were down-regulated in the chondrogenic medium with 10(-7)-10(-5) M nicotine (P < 0.05)."

"the relative cell number (value of OD) was significantly increased at the concentration of 10−6 M [Nicotine] compared to the control in a time-dependent manner"

"blood concentrations of nicotine obtained from chronic cigarette smokers were in the range of 10−8–10−7 M."<-Below the range where nicotine inhibits chondrogenesis at 10-5M.

Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats

"We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg.d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotine exposure induced the inhibition of matrix synthesis and down-regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 μM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner."

"nicotine acts directly on growth plate chondrocytes to suppress hypertrophic differentiation"

"Nicotine treatment of chondrocytes significantly decreased the mRNA expression levels of ECM genes, including aggrecan, Col2A1, and Col1A1"

Nicotine also reduced IGF-1R, IRS1, and Akt1/2.

Smoking affects mRNA expression of bone morphogenetic proteins in human periosteum.

"Smoking has an adverse effect on fracture healing and bone regeneration. The aim of this study was to evaluate the effect of smoking on the expression of the BMPs of human periosteum. Real-time polymerase chain reaction was performed for BMP-2,-4,-6,-7 gene expression in periosteal samples obtained from 45 fractured bones (19 smokers, 26 non-smokers) and 60 non-fractured bones (21 smokers, 39 non-smokers). A hierarchical model of BMP gene expression (BMP-2 > BMP-6 > BMP-4 > BMP-7) was demonstrated in all samples. When smokers and non-smokers were compared, a remarkable reduction in the gene expression of BMP-2, -4 and -6 was noticed in smokers. The comparison of fracture and non-fracture groups demonstrated a higher gene expression of BMP-2, -4 and -7 in the non-fracture samples. Within the subgroups (fracture and non-fracture), BMP gene expression in smokers was either lower but without statistical significance in the majority of BMPs, or similar to that in non-smokers with regard to BMP-4 in fracture and BMP-7 in non-fracture samples. In smokers, BMP gene expression of human periosteum was reduced, demonstrating the effect of smoking at the molecular level by reduction of mRNA transcription of periosteal BMPs."

But can BMP-2 in the periosteum result in ectopic chondrogenesis?

"the suppression of BMP-2, BMP-4 and BMP-7 observed in the fracture group compared with the non-fracture group was not observed in BMP-6 gene expression. The similar mRNA levels of BMP-6 in the two groups indicate the potential role of BMP-6 in the early stages of mesenchymal stem cell differentiation in human periosteum."

"BMP-6 displays significantly more pronounced BMP reporter activation, osteoblast differentiation and stimulation of fracture healing than the most closely related family member, which according to their genetic code is BMP-7."

"in the early phases of osteogenic lineage BMP-7 gene expression is downregulated."