Mechanism of syndesmophyte growth in AS

Ankylosing Spondylitis (AS) causes inflammation around joints and the growth of syndesmophytes that may eventually fuse vertebrae. I'm familiar with the genetics (HLA-B27, IL1A) related to the condition, but I can't find any information about the mechanism that causes the actual growths to occur.

My current assumption is that AS causes the over-production or under-production of a particular compound or enzyme at the growth site, but I can't find any studies or papers that explain this. Is the mechanism known? Is it directly related to abnormal levels of a particular substance?

As far as I remember the pathology course from medical school, chronic long-lasting inflammation often leads to proliferation of connective tussie and ultimately to fibrosis.

The actual mechanism here is the lack of oxygen which is used-up by different immune system cells to produce peroxydes and superoxydes.

Plant Development II: Primary and Secondary Growth

Unlike most animals, who grow to a specific body size and shape and then stop growing (determinate growth), plants exhibit indeterminate growth where the plant will continue adding new organs (leaves, stems, roots) as long as it has access to the necessary resources. Plants are able to continue growing indefinitely like this due to specialized tissues called meristems, which are regions of continuous cell division and growth. Meristematic tissue cells are either undifferentiated or incompletely differentiated, and they continue to produce cells that quickly differentiate, or specialize, and become permanent tissues (dermal, ground, and vascular).

Meristematic tissues consist of three types, based on their location in the plant. Apical meristems contain meristematic tissue located at the tips of stems and roots, which enable a plant to extend in length. Lateral meristems facilitate growth in thickness or girth in a maturing plant. Intercalary (also called basal) meristems occur only in some monocots, at the bases of leaf blades and at nodes (the areas where leaves attach to a stem). This tissue enables the monocot leaf blade to increase in length from the leaf base for example, it allows lawn grass leaves to elongate even after repeated grazing or mowing.

Meristems contribute to both primary (taller/longer) and secondary (wider) growth. Primary growth is controlled by root apical meristems or shoot apical meristems, while secondary growth is controlled by the two lateral meristems, called the vascular cambium and the cork cambium. Not all plants exhibit secondary growth.

The video below provides a nice discussion of primary and secondary growth in plants (beginning at 2:20):

Key Points

Ankylosing spondylitis (AS) is a predominantly genetic disease HLA-B27 is the most important gene

Several HLA-B27-related disease mechanisms are under investigation: the arthritogenic hypothesis, the unfolded protein response hypothesis, and the free heavy chain hypothesis

The non-HLA-B27 genes identified so far might have a role in the processing of HLA-B27 molecules or in cytokine regulation

In addition to inflammation, bone erosion and syndesmophyte formation lead to patient disability in AS, but these processes appear to be uncoupled from inflammation

A major future direction is to understand the processes of bone erosion and syndesmophyte formation in AS, and how these processes can be controlled

Long-term effect of NSAIDs and Biologics on Disease Modification

Observational studies and clinical trials of a disease modification effect of NSAIDs

As there are more than 20 different NSAIDs used in various dosages, an NSAIDs intake index has been developed to quantify the dosage in equivalency and duration of NSAIDs use, with a range of 0 – 100 (34). For example, daily NSAID use equivalent to 150mg diclofenac over the whole study period is scored as 100. Using this index, in the German Spondyloarthritis Inception Cohort (GEPSIC), the odds of mSASSS increase over 2 years was much less (odds ratio = 0.15, 95% confidence interval (CI) 0.02 – 0.96) in patients with high NSAID intake (index >= 50) compared to those with low NSAID intake (index < 50) (total n=88) (35). The results support the hypothesis that NSAIDs have a protective effect on spine radiographic progression in patients with AS. In this study, a similar protective effect was not observed between patients with high versus low AS activity measured by Bath AS Disease Activity Index (BASDAI, Table 1 ) (35), suggesting that subjective symptoms may not be directly associated with radiographic progression, or that the mechanisms by which NSAIDs may act on progression are other than symptom control.

Two separate randomized trials, one with the COX-2 selective NSAID celecoxib, and the other with the non-selective NSAID diclofenac, examined the efficacy of NSAIDs on radiographic progression ( Table 2 ). In the celecoxib trial, TNFi naïve patients with AS were randomized to continuous use vs. on-demand use of celecoxib 100mg twice daily or higher. After 2 years, patients in the continuous use group had less radiographic progression compared to on-demand group (p=0.002) (14). Post hoc analysis of this trial showed that slowing of progression with continuous treatment was greater in patients with elevated inflammatory markers (erythrocyte sedimentation rate or CRP) (36). The diclofenac trial ( E ffects of N SAIDs on RA diographic D amage in A nkylosing S pondylitis (ENRADAS)) used a similar design, in that TNFi naïve patients with AS were randomized to continuous use vs. on-demand use of diclofenac 150mg daily for two years. However, in contrast to the findings in celecoxib study, the continuous group had more progression numerically over two years (p = 0.39). Findings were similar in subgroups of patients with or without syndesmophytes at baseline and in those with or without elevated CRPs (15). The authors stated that despite the fact that “not even a trend for less radiographic progression was seen for the continuous group in our study, it is rather unlikely that inclusion of more patients would have changed the result.”

Table 2.

Comparison of studies on radiographic progression in patients with ankylosing spondylitis.

Author, yearStudy groupsNumber of ParticipantsStudy LengthBaseline mSASSS, mean (SD)Smoking status (%)Male (%)HLA-B27 positivity (%)mSASSS change, mean (SD)
NSAIDs [Randomized controlled Trials]
Wanders, 2005 (14)Continuous celecoxib762 years7.9 (14.7)NR66880.4 (1.7)
On-demand celecoxib742 years9.3 (15.2)NR70881.5 (2.5)
Sieper, 2015 (15)Continuous diclofenac622 years10.9 (15.5)59 * (0.7𠄱.9)
On-demand diclofenac602 years16.4 (18.2)33 * 66.791.70.8 (0.2𠄱.4)
TNFi [Retrospective analyses of clinical trials/long-term extension of clinical trial data]
Baraliakos, 2005 (37)Infliximab412 years12.1NR63900.4(2.7)
GESPIC cohort412 years5.9NR71850.7(2.8)
van der Heijde, 2008 (19)Infliximab2012 years17.7 (17.9)NR78.186.50.9 (2.6)
OASIS1922 years15.8 (18.1)NR67.784.41.0 (3.2)
van der Heijde, 2008 (38)Etanercept2572 years16 (18.3)NR75.578.20.91 (2.45)
OASIS1752 years14 (17.6)NR69.171.10.95 (3.18)
van der Heijde, 2009 (20)Adalimumab3072 years19.8 (19.3)NR76.5NR0.8 (2.6)
OASIS1692 years15.8 (17.6)NR69.2NR0.9 (3.3)
Braun, 2014 (39)Placebo -> Golimumab 50mg66208 weeks16.1 (18.7)NRNRNR2.1 (5.2)
Golimumab 50mg111208 weeks11.7 (16.4)NRNRNR1.3 (4.1)
Golimumab 100mg112208 weeks13.5 (18.9)NRNRNR2.0 (5.6)
IL-17A inhibitor [Retrospective analyses of clinical trials/long-term extension of clinical trial data]
Braun, 2018 (40)Secukinumab 75mg61208 weeks10.7 (17.82)39.387.0NR1.6 (5.67)
Secukinumab 75mg -> 150mg23208 weeks34.870.5NR1.8 (4.32)
Secukinumab 150mg71208 weeks8.6 (16.23)29.663.4NR1.2 (3.91)
Braun, 2019 (23)Secukinumab1682 yearsNR2573.282.960.7% *
ENRADAS cohort692 yearsNR44.966.788.452.2% *
p = 0.2430

NSAID: non-steroidal anti-inflammatory drugs TNFi: tumor necrosis factor inhibitor IL-17A: interleukin-17A GESPIC: German Spondyloarthritis Inception Cohort OASIS: Outcomes in Ankylosing Spondylitis International Study ENRADAS: Effects of NSAIDs on Radiographic Damage in Ankylosing Spondylitis SD: standard deviation NR: not reported.

The results from both studies might suggest that only COX-2 selective NSAIDs have a disease modification effect, but several caveats should be considered. First, absence of a dose effect makes the trial results difficult to interpret. When using mSASSS change as the study outcome, at least two years are proposed to detect a significant change with a sample size of 100 patients in each treatment arm. Because it would be unethical to conduct placebo-controlled trials lasting 2 years, both NSAIDs trials compared continuous use versus on-demand use, to approximate the ideal placebo-controlled study, with the intention to see whether the difference in NSAID intake between the two groups was correlated with the difference in mSASSS increase. The result from the celecoxib trial did show a lower rate of mSASSS increase with continuous use, however, a dose effect of NSAIDs was not demonstrated. The average dose in the continuous group (243mg) was only modestly higher than the on-demand group (201mg), despite the significant difference in the outcome (mean mSASSS change +0.4 in the continuous group vs. +1.5 in the on-demand group). The diclofenac trial groups had a difference in NSAID dose, with NSAIDs indices of 77 in the continuous group vs. 44 in the on-demand group, but did not show a corresponding decrease in radiographic progression (mean mSASSS change +1.3 in the continuous group vs. +0.8 in the on-demand group).

Further, in the event of imbalance in randomization, risk factors that are associated with spine radiographic progression could lead to bias when assessing treatment effects. For example, in the diclofenac study, the continuous use group had a significantly higher proportion of current smokers at baseline, compared to the on-demand group. Whether the difference in smoking between the groups was enough to overwhelm a potential inhibitory effect of continuous diclofenac use is unclear (15).

A third clinical trial (CONSUL trial, <"type":"clinical-trial","attrs":<"text":"NCT02758782","term_id":"NCT02758782">> NCT02758782), which evaluates the effect of celecoxib with golimumab compared to golimumab alone on radiographic progression in patients with AS, is ongoing.

Disease modification effects of biologics

With regard to biologics, two strategies have been taken to retrospectively analyze radiographic data from long-term extensions of clinical trials. The first strategy was to compare the radiographic progression among participants in biologic trials to that of biologic-naïve, historical cohorts ( Table 2 ) (19,20,23,37,38). Most of these studies used mSASSS change over 2 years as the primary radiographic endpoint, and did not find any significant difference in radiographic progression between groups. One of the studies, secukinumab vs. ENRADAS cohort used the proportion of patients with no radiographic progression (defined as least square mean change of mSASSS <= 0) as the endpoint, and reported a suggestion toward more non-progressors in the secukimunab group (60.7% vs 52.2%, p = 0.2430). Notably, the inter-reader agreement for mSASSS change of this study was poor (k = 0.17), and ENRADAS cohort had a much higher percentage of smokers (23).

The second strategy, similar to the NSAIDs trials, was to compare different dosing regimens with the question of whether there was a dose effect ( Table 2 ) (39,40). However, this approach has not shown associations between the dose of biologics and progression. In the 4-year secukinumab study (Braun 2018), although the 150mg group had marginally less radiographic progression than the 75mg groups by mSASSS, the 75mg groups had higher mSASSS at baseline, which is a risk factor for radiographic progression (40). In addition, similar proportions of patients in each dosing group (78.9% vs. 78.6%) had no radiographic progression (mSASSS change <= 2)., in the open label extension of Certolizumab study, 80.6% patients had no radiographic progression at 4 years, although there was no comparison group (41).

Two observational studies examined the effect of TNFi on spine radiographic progression, with somewhat conflicting results. In a prospective cohort of 334 patients with AS in North America, after adjustment for baseline mSASSS and propensity to receive TNFi, patients who were on a TNFi had a 50% lower odds of progression compared to those who never received TNFi. Also, patients who took TNFi for a larger proportion of their disease course had less mSASSS progression (42). In contrast, in a recent observational study of 432 patients with AS from the Swiss Clinical Quality Management Cohort, no contemporaneous association between TNFi use and radiographic progression (43). Instead, treatment with TNFi prior to the radiographic interval was protective, as was longer duration of prior use of TNFi. The data did not detect an association with TNFi during the radiographic interval, perhaps indicating that prolonged treatment is needed to see an effect (43).

In summary, current evidence for a disease-modifying effect of biologics, including TNFi and IL-17 inhibitors, is lacking and the effect of the different classes of biologics on radiographic progression has not been compared directly. A direct comparison of secukinumab to an adalimumab biosimilar on radiographic progression is on-going ( <"type":"clinical-trial","attrs":<"text":"NCT03259074","term_id":"NCT03259074">> NCT03259074).

3. FGF Signaling

FGFs act as signal molecules that bind and activate FGFRs. Activated FGFRs mediate signaling by recruiting specific molecules that bind to phosphorylated tyrosine at the cytosolic part of the receptor, triggering a number of signaling pathways leading to specific cellular responses. These then serve as docking sites for the recruitment of SH2 (Src homology-2) or PTB (phosphotyrosine binding) domains of adaptors docking proteins or signaling enzymes. Signaling complexes are formed and recruited to the active receptors resulting in a cascade of phosphorylation events [20]. The best understood pathways are the RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway. Figure 2 schematically describes the three pathways of the FGF signal, the RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway.

FGF signal pathway. FGFs stimulate tyrosine phosphorylation of the docking protein FRS, followed by forming the GRB2-SHP2-GAB-1 complex resulting in activation of RAS-MAP kinase pathway and PI3 kinase/AKT pathway. In PLCγ pathway, activated PLCγ hydrolyzes phosphatidylinositol, generating IP3 and DAG and results in the activation of PKC. FRS2: fibroblast growth factor receptor substrate 2, GRB: guanine nucleotide exchange factor, SOS: son of sevenless, RAS: monomeric G-protein, RAF: kinase, MEK: kinase, MKP1: MAP kinase phosphatase, PIP2: phosphatidylinositol (4,5)-bisphosphate, IP3: inositol triphosphate, DAG: diacylglycerol, PKC: protein kinase C.

3.1. RAS/MAP Kinase Pathway

Mitogen-activated protein (MAP) kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli (mitogens) and regulate various cellular activities such as gene expression, mitosis, differentiation, and cell survival/apoptosis [21]. c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK), and p38 mitogen-activated kinase are examples of effectors MAP kinase [22]. Interestingly, the activation of ERK 1/2 and p38 in response to FGF has been observed in all cell types, while the activities of other signal transduction pathways vary depending on the cell type.

To date, the main pathway of the FGF signal is the RAS/MAP kinase pathway, which contains many signaling proteins. A key event in the FGF signaling pathway is phosphorylation of the tyrosine residues of the docking protein, fibroblast growth factor receptor substrate 2α (FRS2α), which provides new binding sites for direct or indirect recruitment of proteins that are responsible for both activation and attenuation of signaling [23, 24]. FRS2α recruits a complex consisting of an adaptor protein, the guanine nucleotide exchange factor 2 (GRB2), the son of sevenless (SOS), the tyrosine phosphatase (SHP2), and the docking protein, GRB2-associated binding protein 1 (GAB1). Formation of the FRS2 signaling complex results in activation of RAS/MAP kinase [25] as well as PI3 kinase/AKT pathways [26]. The RAS-MAP kinase pathway has been implicated in cell growth and differentiation in many studies [11].

Lax et al. [24] showed that FGF signals induce a MAP kinase mediated negative feedback loop that causes threonine phosphorylation of FRS2a, leading to a reduction of its tyrosine phosphorylation and decreased recruitment of GRB2. Receptor tyrosine kinases also induce negative signals via activation of the sprouty proteins that inhibit the recruitment of GRB2-SOS complexes to FRS2 and the receptor and attenuate the RAS-MAP kinase pathway. Members of the Sef and MAP kinase phosphatase families are other negative modulators of FGF signaling, while XFLRT3, a member of a leucine-rich-repeat transmembrane protein family, is a novel positive modulator. Expression of XFLRT3 is induced by FGF and down-regulated after inhibition of FGF signaling [27]. Thus, FGF signaling is modulated by both positive and negative mechanisms, and subtle modulations in the signal are important determinants of the biological response during development.

3.2. PI3 Kinase/AKT Pathway

Similar to the RAS/MAP kinase pathway, the phosphoinositide 3 (PI3) kinase/AKT pathway is initiated by forming an FRS2 signaling complex. Next, GAB1 protein links activated FGF receptors with PI3 kinase. GAB1 consists of a pleckstrin homology domain, a proline-rich region, and multiple tyrosine phosphorylation sites that serve as binding sites for the SH2 domains. The p110 catalytic subunit of PI3 kinase is in a complex with an adaptor protein (p85) that has two SH2 domains thus, p85 binds to phosphorylated tyrosine residues in GAB1 adaptor protein. Phosphoinositide-dependent kinase and the anti-apoptotic protein kinase AKT are activated downstream of the PI3 kinase [26].

The PI3 kinase/AKT pathway is implicated in cell survival and cell fate determination, as well as the PI3 kinase/aPKC signaling cascade in cell polarity control [11]. Böttcher et al. [27] showed that GAB1 is required for stimulation of the AKT pathway by FGF.

3.3. PLCγ Pathway

One of the target molecules for activated FGFR is phospholipase C gamma (PLCγ), which binds to the phosphorylated Tyr-766 of the receptor and then becomes tyrosine phosphorylation of PLCγ, resulting in PLCγ activation. Activated PLCγ hydrolyzes phosphatidylinositol, generating inositol triphosphate (IP3) and diacylglycerol (DAG) [28]. IP3 is a cellular second messenger that facilitates the release of calcium from the endoplasmic reticulum. Increased levels of calcium in the cytosol and DAG together activate protein kinase C (PKC). The physiological relevance of this pathway is not obvious since its disruption does not abolish either mitogenesis [29] or cell differentiation [30]. However, some data indicate that it may be necessary for adhesion, at least in some cell types [31].

Mechanism of syndesmophyte growth in AS - Biology

Article Reviewed:
Charge, S. B. P., and Rudnicki, M.A. (2004). Cellular and molecular regulation of muscle regeneration. Physiological Reviews, Volume 84, 209-238.

Personal trainers and fitness professionals often spend countless hours reading articles and research on new training programs and exercise ideas for developing muscular fitness. However, largely because of its physiological complexity, few fitness professionals are as well informed in how muscles actually adapt and grow to the progressively increasing overload demands of exercise. In fact, skeletal muscle is the most adaptable tissue in the human body and muscle hypertrophy (increase in size) is a vastly researched topic, yet still considered a fertile area of research. This column will provide a brief update on some of the intriguing cellular changes that occur leading to muscle growth, referred to as the satellite cell theory of hypertrophy.

Trauma to the Muscle: Activating The Satellite Cells
When muscles undergo intense exercise, as from a resistance training bout, there is trauma to the muscle fibers that is referred to as muscle injury or damage in scientific investigations. This disruption to muscle cell organelles activates satellite cells, which are located on the outside of the muscle fibers between the basal lamina (basement membrane) and the plasma membrane (sarcolemma) of muscles fibers to proliferate to the injury site (Charge and Rudnicki 2004). In essence, a biological effort to repair or replace damaged muscle fibers begins with the satellite cells fusing together and to the muscles fibers, often leading to increases in muscle fiber cross-sectional area or hypertrophy. The satellite cells have only one nucleus and can replicate by dividing. As the satellite cells multiply, some remain as organelles on the muscle fiber where as the majority differentiate (the process cells undergo as they mature into normal cells) and fuse to muscle fibers to form new muscle protein stands (or myofibrils) and/or repair damaged fibers. Thus, the muscle cells’ myofibrils will increase in thickness and number. After fusion with the muscle fiber, some satellite cells serve as a source of new nuclei to supplement the growing muscle fiber. With these additional nuclei, the muscle fiber can synthesize more proteins and create more contractile myofilaments, known as actin and myosin, in skeletal muscle cells. It is interesting to note that high numbers of satellite cells are found associated within slow-twitch muscle fibers as compared to fast-twitch muscle fibers within the same muscle, as they are regularly going through cell maintenance repair from daily activities.

Growth factors
Growth factors are hormones or hormone-like compounds that stimulate satellite cells to produce the gains in the muscle fiber size. These growth factors have been shown to affect muscle growth by regulating satellite cell activity. Hepatocyte growth factor (HGF) is a key regulator of satellite cell activity. It has been shown to be the active factor in damaged muscle and may also be responsible for causing satellite cells to migrate to the damaged muscle area (Charge and Rudnicki 2004).
Fibroblast growth factor (FGF) is another important growth factor in muscle repair following exercise. The role of FGF may be in the revascularization (forming new blood capillaries) process during muscle regeneration (Charge and Rudnicki 2004).
A great deal of research has been focused on the role of insulin-like growth factor-I and –II (IGFs) in muscle growth. The IGFs play a primary role in regulating the amount of muscle mass growth, promoting changes occurring in the DNA for protein synthesis, and promoting muscle cell repair.
Insulin also stimulates muscle growth by enhancing protein synthesis and facilitating the entry of glucose into cells. The satellite cells use glucose as a fuel substrate, thus enabling their cell growth activities. And, glucose is also used for intramuscular energy needs.

Growth hormone is also highly recognized for its role in muscle growth. Resistance exercise stimulates the release of growth hormone from the anterior pituitary gland, with released levels being very dependent on exercise intensity. Growth hormone helps to trigger fat metabolism for energy use in the muscle growth process. As well, growth hormone stimulates the uptake and incorporation of amino acids into protein in skeletal muscle.
Lastly, testosterone also affects muscle hypertrophy. This hormone can stimulate growth hormone responses in the pituitary, which enhances cellular amino acid uptake and protein synthesis in skeletal muscle. In addition, testosterone can increase the presence of neurotransmitters at the fiber site, which can help to activate tissue growth. As a steroid hormone, testosterone can interact with nuclear receptors on the DNA, resulting in protein synthesis. Testosterone may also have some type of regulatory effect on satellite cells.

Muscle Growth: The ‘Bigger’ Picture
The previous discussion clearly shows that muscle growth is a complex molecular biology cell process involving the interplay of numerous cellular organelles and growth factors, occurring as a result of resistance exercise. However, for client education some important applications need to be summarized. Muscle growth occurs whenever the rate of muscle protein synthesis is greater than the rate of muscle protein breakdown. Both, the synthesis and breakdown of proteins are controlled by complimentary cellular mechanisms. Resistance exercise can profoundly stimulate muscle cell hypertrophy and the resultant gain in strength. However, the time course for this hypertrophy is relatively slow, generally taking several weeks or months to be apparent (Rasmussen and Phillips, 2003). Interestingly, a single bout of exercise stimulates protein synthesis within 2-4 hours after the workout which may remain elevated for up to 24 hours (Rasmussen and Phillips, 2003). Some specific factors that influence these adaptations are helpful to highlight to your clients.

All studies show that men and women respond to a resistance training stimulus very similarly. However, due to gender differences in body size, body composition and hormone levels, gender will have a varying effect on the extent of hypertrophy one may possibly attain. As well, greater changes in muscle mass will occur in individuals with more muscle mass at the start of a training program.

Aging also mediates cellular changes in muscle decreasing the actual muscle mass. This loss of muscle mass is referred to as sarcopenia. Happily, the detrimental effects of aging on muscle have been shown be restrained or even reversed with regular resistance exercise. Importantly, resistance exercise also improves the connective tissue harness surrounding muscle, thus being most beneficial for injury prevention and in physical rehabilitation therapy.

Heredity differentiates the percentage and amount of the two markedly different fiber types. In humans the cardiovascular-type fibers have at different times been called red, tonic, Type I, slow-twitch (ST), or slow-oxidative (SO) fibers. Contrariwise, the anaerobic-type fibers have been called the white, phasic, Type II, fast-twitch (FT), or fast-glycolytic (FG) fibers. A further subdivision of Type II fibers is the IIa (fast-oxidative-glycolytic) and IIb (fast-glycolytic) fibers. It is worthy of note to mention that the soleus, a muscle involved in standing posture and gait, generally contains 25% to 40% more Type I fibers, while the triceps has 10% to 30% more Type II fibers than the other arm muscles (Foss and Ketyian, 1998). The proportions and types of muscle fibers vary greatly between adults. It is suggested that the new, popular periodization models of exercise training, which include light, moderate and high intensity training phases, satisfactorily overload the different muscle fiber types of the body while also providing sufficient rest for protein synthesis to occur.

Muscle Hypertrophy Summary
Resistance training leads to trauma or injury of the cellular proteins in muscle. This prompts cell-signaling messages to activate satellite cells to begin a cascade of events leading to muscle repair and growth. Several growth factors are involved that regulate the mechanisms of change in protein number and size within the muscle. The adaptation of muscle to the overload stress of resistance exercise begins immediately after each exercise bout, but often takes weeks or months for it to physically manifest itself. The most adaptable tissue in the human body is skeletal muscle, and it is remarkably remodeled after continuous, and carefully designed, resistance exercise training programs.

Cell length growth patterns in fission yeast reveal a novel size control mechanism operating in late G2 phase

Because cylindrically shaped fission yeast cells grow exclusively at their tips, cell volume is proportional to length and can be easily monitored by time-lapse microscopy. Here, we analysed the growth pattern of individual cells from several fission yeast strains to determine the growth function that describes them most adequately and to perform size control studies.


The growth pattern of most cells during their growth period is best described by a bilinear function (i.e., two linear segments of different growth rates separated by a rate-change point). Linear growth patterns were also observed in several cases, but exponential ones only rarely. Since the bilinear patterns are separated into two segments by a breakpoint, we examined the existence of size control by regression analyses of the appropriate growth parameters in both segments. This confirmed the existence of known size controls in late G1, mid-G2 and late G2 during the fission yeast cycle. The present analyses also revealed that, contrary to the commonly accepted current view, late G2 size control is a general characteristic third event in the cycle. The level of the critical late G2 size that needs to be reached in an individual fission yeast cell is influenced by the growth rate of the cell in a manner similar to budding yeast, suggesting an evolutionary conserved mechanism.


The present study of individual cell growth patterns in wild-type and several cell cycle mutant fission yeast strains confirmed that, for most cells, growth is best described by a bilinear function. Three different size control mechanisms were found to operate in the different strains, and, as a novel observation, cell size was always found to be monitored before mitotic onset, irrespective of the existence of any earlier size checkpoints.


Studying the pattern of growth and the mechanism of size control helps to clarify the connections between cell growth and division, since their coordination must work properly to maintain size homeostasis. In this study, we argue that most individual fission yeast cells grow following a bilinear pattern, and we confirm the existence of three different size control mechanisms.

Mechanism of syndesmophyte growth in AS - Biology

Introduction The molecular mechanisms of syndesmophyte formation in ankylosing spondylitis (AS) are yet to be characterised. Molecules involved in bone formation such as Wnt proteins and their antagonists probably drive syndesmophyte formation in AS.

Methods This study investigated sequential serum levels of functional dickkopf-1 (Dkk1), a potent Wnt antagonist involved in bone formation in arthritis, by capture ELISA with its receptor LRP6 in 65 AS patients from the German Spondyloarthritis Inception Cohort. Dkk1 levels were then related to structural progression (syndesmophyte formation) as well as sclerostin and C-reactive protein (CRP) levels.

Results Functional Dkk1 levels were significantly (p=0.025) higher in patients with no syndesmophyte growth (6.78±5.48 pg/ml) compared with those with syndesmophyte growth (4.13±2.10 pg/ml). Dkk1 levels were highly correlated to serum sclerostin levels (r=0.71, 95% CI 0.53 to 0.82 p<0.001) but not to CRP (r=0.15, 95% CI −0.10 to 0.38 p=0.23).

Conclusion AS patients with no syndesmophyte formation show significantly higher functional Dkk1 levels suggesting that blunted Wnt signalling suppresses new bone formation and consequently syndesmophyte growth and spinal ankylosis. Similar to serum sclerostin levels, the functional Dkk1 level thus emerges as a potential biomarker for structural progression in patients with AS


Adhesion Cartoons

Adhesion EM Images

Differential positioning of adherens junctions is associated with initiation of epithelial folding

Nature. 2012 Mar 28. doi: 10.1038/nature10938.

Wang YC, Khan Z, Kaschube M, Wieschaus EF. Source 1] Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA [2] Howard Hughes Medical Institute, Princeton University, Princeton, New Jersey 08544, USA.

"During tissue morphogenesis, simple epithelial sheets undergo folding to form complex structures. The prevailing model underlying epithelial folding involves cell shape changes driven by myosin-dependent apical constriction. Here we describe an alternative mechanism that requires differential positioning of adherens junctions controlled by modulation of epithelial apical-basal polarity. Using live embryo imaging, we show that before the initiation of dorsal transverse folds during Drosophila gastrulation, adherens junctions shift basally in the initiating cells, but maintain their original subapical positioning in the neighbouring cells. Junctional positioning in the dorsal epithelium depends on the polarity proteins Bazooka and Par-1. In particular, the basal shift that occurs in the initiating cells is associated with a progressive decrease in Par-1 levels. We show that uniform reduction of the activity of Bazooka or Par-1 results in uniform apical or lateral positioning of junctions and in each case dorsal fold initiation is abolished. In addition, an increase in the Bazooka/Par-1 ratio causes formation of ectopic dorsal folds. The basal shift of junctions not only alters the apical shape of the initiating cells, but also forces the lateral membrane of the adjacent cells to bend towards the initiating cells, thereby facilitating tissue deformation. Our data thus establish a direct link between modification of epithelial polarity and initiation of epithelial folding."

Wang YC, Khan Z, Kaschube M & Wieschaus EF. (2012). Differential positioning of adherens junctions is associated with initiation of epithelial folding. Nature , 484, 390-3. PMID: 22456706 DOI.

Role of the gut endoderm in relaying left-right patterning in mice

PLoS Biol. 2012 Mar10(3):e1001276. Epub 2012 Mar 6. Viotti M, Niu L, Shi SH, Hadjantonakis AK. Source Developmental Biology Program, Sloan-Kettering Institute, New York, New York, United States of America.

"Establishment of left-right (LR) asymmetry occurs after gastrulation commences and utilizes a conserved cascade of events. In the mouse, LR symmetry is broken at a midline structure, the node, and involves signal relay to the lateral plate, where it results in asymmetric organ morphogenesis. How information transmits from the node to the distantly situated lateral plate remains unclear. Noting that embryos lacking Sox17 exhibit defects in both gut endoderm formation and LR patterning, we investigated a potential connection between these two processes. We observed an endoderm-specific absence of the critical gap junction component, Connexin43 (Cx43), in Sox17 mutants. Iontophoretic dye injection experiments revealed planar gap junction coupling across the gut endoderm in wild-type but not Sox17 mutant embryos. They also revealed uncoupling of left and right sides of the gut endoderm in an isolated domain of gap junction intercellular communication at the midline, which in principle could function as a barrier to communication between the left and right sides of the embryo. The role for gap junction communication in LR patterning was confirmed by pharmacological inhibition, which molecularly recapitulated the mutant phenotype. Collectively, our data demonstrate that Cx43-mediated communication across gap junctions within the gut endoderm serves as a mechanism for information relay between node and lateral plate in a process that is critical for the establishment of LR asymmetry in mice."

Viotti M, Niu L, Shi SH & Hadjantonakis AK. (2012). Role of the gut endoderm in relaying left-right patterning in mice. PLoS Biol. , 10, e1001276. PMID: 22412348 DOI.

The Institute for Creation Research

The concept of natural selection remains controversial in both the evolutionary and creationist communities. Classical evolutionists still cannot clearly define it as they continue to debate one another over a valid model and definition. Meanwhile, secular molecular biologists are content to leave the debate primarily in the hands of the classical biologists when the hard data needed to validate natural selection in one form or another ultimately lies at the molecular level. This is typical of the compartmentalized nature of modern academics where scientists focus on a single area of specialty research and assume that some other sector of biology will solve the serious problems of Darwinian evolution.

The lack of a clearly defined molecular mechanism to create new irreducibly complex traits as a creative force in evolution is why many scientists have had difficulty characterizing Darwin&rsquos concept for over 70 years. Dr. Randy Guliuzza recently pointed out the various key philosophical and semantic anomalies of the confusing quagmire surrounding the usage of natural selection terminology. 1 Dr. Guliuzza not only exposed the various obfuscated semantics involved, but he also fully substantiated his deductions by quoting the evolutionists in their own words. 2

The next and perhaps most important step following Dr. Guliuzza&rsquos effort is for the ICR biological sciences team to begin illustrating the many interesting cellular mechanisms that allow organisms to adapt to new environments or changes in their existing environments. To some extent, this has already been going on through ICR biologist Brian Thomas&rsquo daily news articles and other ICR bio-scientists&rsquo publications in various journals and in Acts & Facts.

Most expressed traits and adaptations are biologically complex responses. These adaptations can be defined as biological interactions at the environmental interface that are regulated by genetic programming and cell physiology. A creationist model of adaptation is based on an organism&rsquos innate physiological capabilities and fault tolerance mechanisms that are genetically programmed by the Creator. Scientifically valid descriptions of adaptation employ recent molecular discoveries in genomics, cell physiology, and phenotypic plasticity to explain how living creatures successfully interface with environmental challenges and fill ecological niches.

Environmental stresses and stimuli cannot exercise the creative causation of highly complex pre-coded genetic information that underlies irreducibly complex systems of adaptation. Organismal interaction with the environment involves highly complex and dynamic physiological and genetic responses to a wide range of physical and chemical sensory cues. These environmental cues are perceived by complex systems of cell sensor networks that interact with an organism&rsquos highly engineered genetic system. While adaptation systems are complex and flexible, they are not evolvable on a grand neo-Darwinian scale. They are pre-engineered, pre-programmed, and irreducibly complex in the strictest sense of the term, and they unequivocally imply the infinite intelligence of our Creator God.

An upcoming research column will discuss the concept of genetic diversity in biological adaptation. For a review of genetic diversity at an introductory level, see the recent ICR publication by Parker and Tomkins. 3

  1. See Guliuzza, R.J. 2012. Darwin&rsquos Sacred Imposter: Answering Questions about the Fallacy of Natural Selection. Acts & Facts. 41 (2): 12-15.
  2. Guliuzza, R. 2011. Darwin&rsquos Sacred Imposter: Recognizing Missed Warning Signs. Acts & Facts. 40 (5): 12-15 Guliuzza, R. 2011. Darwin&rsquos Sacred Imposter: How Natural Selection Is Given Credit for Design in Nature. Acts & Facts. 40 (7): 12-15 Guliuzza, R. 2011. Darwin&rsquos Sacred Imposter: The Illusion That Natural Selection Operates on Organisms. Acts & Facts. 40 (9): 12-15 Guliuzza, R. 2011. Darwin&rsquos Sacred Imposter: Natural Selection&rsquos Idolatrous Trap. Acts & Facts. 40 (11): 12-15.
  3. Parker, G. and J. Tomkins. 2010. Genetic Diversity. Dallas, TX: Institute for Creation Research.

* Dr. Tomkins is Research Associate at the Institute for Creation Research and received his Ph.D. in Genetics from Clemson University.

Cite this article: Tomkins, J. 2012. Mechanisms of Adaptation in Biology: Molecular Cell Biology. Acts & Facts. 41 (4): 6.