I wrote about CHOP before here.

Here’s some new studies about CHOP and longitudinal bone growth:

Abnormal Chondrocyte Apoptosis in the Cartilage Growth Plate is Influenced by Genetic Background and Deletion of CHOP in a Targeted Mouse Model of Pseudoachondroplasia.

“Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia caused by mutations in cartilage oligomeric matrix protein (COMP) and characterised by short limbed dwarfism and early onset osteoarthritis. Mouse models of PSACH show variable retention of mutant COMP in the ER of chondrocytes, however, in each case a different stress pathway is activated and the underlying disease mechanisms remain largely unknown. T585M COMP mutant mice are a model of moderate PSACH and demonstrate a mild ER stress response. Although mutant COMP is not retained in significant quantities within the ER of chondrocytes, both BiP and the pro-apoptotic ER stress-related transcription factor CHOP are mildly elevated, whilst bcl-2 levels are decreased, resulting in increased and spatially dysregulated chondrocyte apoptosis. To determine whether the abnormal chondrocyte apoptosis observed in the growth plate of mutant mice is CHOP-mediated, we bred T585M COMP mutant mice with CHOP-null mice to homozygosity, and analysed the resulting phenotype. Although abnormal apoptosis was alleviated in the resting zone following CHOP deletion, the mutant growth plates were generally more disorganised. Furthermore, the bone lengths of COMP mutant CHOP null mice were significantly shorter at 9 weeks of age when compared to the COMP mutant mice, including a significant difference in the skull length.{So you don’t want to inhibit CHOP is you want to grow taller} Overall, these data demonstrate that CHOP-mediated apoptosis is an early event in the pathobiology of PSACH and suggest that the lack of CHOP, in conjunction with a COMP mutation, may lead to aggravation of the skeletal phenotype via a potentially synergistic effect on endochondral ossification. ”

So CHOP increasing apoptosis is critical for optimal longitudinal bone growth.

“CHOP can be activated via the PERK and ATF6 unfolded protein response (UPR) pathways and acts to decrease the levels of the anti-apoptotic protein bcl-2, which subsequently renders the cells more susceptible to programmed cell death”

“In contrast, the length of the skull, which is formed through a combination of endochondral and intramembranous ossification, was 4.7% shorter in CHOP null mice at 9 weeks of age when compared to the wild type controls”

There was no significant differences between bone length in pelvic, femur, and tibia bone but there didn’t seem to be any trends either way.  But at 9 weeks it’s possible that CHOP null mice were longer than mice were CHOP was present in the other bones.

CHOP deletion exaserbated dwarfism though.

Overexpression of Wnt11 promotes chondrogenic differentiation of bone marrow-derived mesenchymal stem cells in synergism with TGF-β

“Wnt signaling involves regulating chondrogenesis and MSC differentiation. The aim of the present study was to investigate the role of Wnt11, a member of noncanonical Wnts, in MSCs during chondrogenic differentiation. Overexpression of Wnt11 inhibited proliferation of MSCs and caused a G0/G1 cell cycle arrest. The expression level of chondrogenic markers, aggrecan and Collagen II, was significantly increased in MSCs transduced with Wnt11 as compared with non-transduced cells or MSCs transduced with the empty lentiviral vector. Furthermore, ectopic expression of Wnt11 stimulated gene expression of chondrogenic regulators, SRY-related gene 9, Runt-related transcription factor 2, and Indian hedgehog. Finally, Wnt11 overexpression promoted chondrogenic differentiation of MSCs in synergism with TGF-β.”

“Wnt3a promotes proliferation whereas suppresses chondrogenic differentiation of MSCs. In addition, expression of either Wnt-1 or Wnt7a causes a severe block in chondrogenesis”

“Wnt11 gene is highly expressed at the late stage of chondrogenic differentiation of human MSCs in three-dimensional alginate gels”

“the inhibition rate of Wnt11 overexpression for MSC proliferation was relatively low”

“Wnt11 may enhance the chondrogenic differentiation of MSCs via repressing canonical Wnt signaling, such as Wnt1 and Wnt3a, which has been shown to inhibit chondrogenic differentiation of MSCs”

Identification and Functional Characterization of Two Novel NPR2 Mutations in Japanese Patients with Short Stature.

“C-type natriuretic peptide (CNP) – natriuretic peptide receptor B (NPR-B) signaling is critical for endochondral ossification, which is responsible for longitudinal growth in limbs and vertebrae. Biallelic NPR2 mutations cause acromesomelic dysplasia, type Maroteaux, which is bone dysplasia characterized by severe short stature and short limbs. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. Objective: The goal of this study was to identify and characterize NPR2 mutations among Japanese patients with short stature. SWe enrolled 101 unrelated Japanese patients with short stature. NPR2 and NPPC were sequenced, and the identified variants were characterized in vitro. In two subjects, we identified two novel heterozygous NPR2 mutations (R110C and Q417E) causing a loss of CNP-dependent cGMP generation capacities and having dominant negative effects. R110C was defective in trafficking from the endoplasmic reticulum to the Golgi apparatus. In contrast, Q417E showed clear cell surface expression.  We identified heterozygous NPR2 mutations in 2% of Japanese patients with short stature. Our in vitro findings indicate that NPR2 mutations have a dominant negative effect, and their dominant negative mechanisms vary corresponding to the molecular pathogenesis of the mutations.”

“a gain-of-function NPR2 mutation was identified in patients with tall stature and macrodactyly”

“the effect of a heterozygous NPR2 mutation on height SDS is–1.8 according to the previous report, 2.6 in 100 subjects with short stature, which is defined as height SDS less than –2.0, are expected to be heterozygous for the NPR2 mutation.”

An increase in articular cartilage thickness will result in a slight increase in height.  There have been studies that show that mechanical loading can increase this cartilage thickness in some bones.  Whether the articular cartilage can increase in thickness could be affected by whether it is bound by the periosteum or not.  Some bones such as the fingers can grow longer and are not bound by periosteum.

Longitudinal change in femorotibial cartilage thickness and subchondral bone plate area in male and female adolescent vs. mature athletes.

“The objective of this study was to explore longitudinal change in femorotibial cartilage thickness and tAB[Subchondral bone area] in adolescent athletes, and to compare these data with those of mature former athletes. Twenty young (baseline age 16.0±0.6 years) and 20 mature (46.3±4.7 years) volleyball athletes were studied (10 men and 10 women in each group). Magnetic resonance images were acquired at baseline and at year 2-follow-up, and longitudinal changes in cartilage thickness and tAB were determined quantitatively after segmentation. The yearly increase in total femorotibial cartilage thickness was 0.8% in young men and 1.4% in young women; the gain in tAB was 0.4% and 0.7%, respectively. The cartilage thickness increase was greatest in the medial femur, and was not significantly associated with the variability in tAB growth. Mature athletes showed smaller gains in tAB, and lost >1% of femorotibial cartilage per annum[year], with the greatest loss observed in the lateral tibia. In conclusion, we find an increase in cartilage thickness (and some in tAB) in young athletes toward the end of adolescence. Mature (former) athletes displayed high rates of (lateral) femorotibial cartilage loss, potentially due to a high prevalence of knee injuries.”

“X-rays are not capable of delineating soft tissues and cartilage”

“articular cartilage volume growth in the tibia (but not in the patella) correlated significantly with change in body height, and that – in terms of cartilage volume gain – overweight children did not differ significantly from those with normal weight. Finally, tibial cartilage volume gain was greater in those who reported an average intensity of sport above the median”

“a longitudinal gain in cartilage volume and thickness was observed post-injury[ACL rupture] and was interpreted as a potential sign of (pathological) cartilage swelling”

Comparison of adolescent and mature volleyball player knee by MRI.

“Adolescent men and women tended to have smaller cartilage thickness than mature participants in the medial femorotibial compartment, but greater thickness than mature adults in the lateral compartmen”

“Lateral compartment cartilage was thicker than medial compartment cartilage across all sex and age strata. Medially, the femoral cartilage was thicker compared to the tibial cartilage, while laterally, the tibial cartilage thickness was thicker compared to the medial cartilage; again, this was consistent across all sex and age strata”

“the study lacks a reference group of less physically active adults without knee injuries”

Perichondrium is key to regenerative potential of articular cartilage and unfortunately it does not cover the joint region.

If you can correct scoliosis partially by stimulating growth bilaterally than you can grow taller by stimulating growth on the spine unilaterally.  Unfortunately, this study seems to only study reduction in height.

Biomechanical Simulation and Analysis of Scoliosis Correction using a Fusionless Intravertebral Epiphyseal Device.

“Computer simulations to analyze the biomechanics of a novel compression-based fusionless device (hemi-staple) that does not cross the disc for the treatment of adolescent idiopathic scoliosis.Objective. To biomechanically model, simulate and analyze the hemi-staple action using a human finite element model (FEM).Summary of Background Data. A new fusionless growth sparing instrumentation device (hemi-staple), which locally compresses the growth plate without spanning the disc, was previously developed and successively tested on different animal models.Methods. Patient specific FEMs of the spine, ribcage and pelvis were built using radiographs of 10 scoliotic adolescents (11.7±0.9yrs; Cobb thoracic:35°±7°, lumbar:24°±6°). A validated algorithm allowed simulating the growth (0.8-1.1mm/yr/vertebra){There are 33 vertebrae.  So that would 33 mm of height per year and 66 mm over a 2 year period so about 20% of an inch in height} and growth modulation process (Hueter-Volkmann principle) over a period of 2 years. Four instrumentation configurations on the convex curves were individually simulated (Config#1: 5 thoracic vertebrae with hemi-staples on superior endplates; Config#2: same as Conf#1 with hemi-staples on both endplates; Config#3: same as Config#1 +4 lumbar vertebrae; Config#4: same as Config#2 +4 lumbar vertebrae).Results. Without hemi-staples, on average the thoracic and lumbar Cobb angles respectively progressed from 35° to 56°, and 24° to 30°, while the vertebral wedging at curve apices progressed from 5° to 12°. With the hemi-staple Config#1, the Cobb angles progressed, but were limited to 42° and 26°, while the wedging ended at 8°. With Config#3, Cobb and wedging were kept nearly constant (38°, 21°, 7°). With hemi-staples on both endplates (Config#2, Config#4), the Cobb and wedging were all reduced (thoracic Cobb for Config#2 and #4: 24° and 15°; lumbar Cobb: 21° and 11°; wedging: 2° and 1°).Conclusion. This study suggests that the hemi-staple has the biomechanical potential to control the scoliosis progression and highlights the importance of the instrumentation configuration to correct the spinal deformities. It biomechanically supports the new fusionless device concept as an alternative for the early treatment of idiopathic scoliosis.”

“Simulated instrumentation of both growth plates on the convex side of the scoliotic curve
allows the optimal correction”

“The ratio of expected vertebral longitudinal growth rates (Gm: 0.8 – 1.1 mm/yr) [related] according to the difference in magnitudes between scoliotic stress in the growth plate (σ) and regular physiological stress (σm).”

“With the hemi-staple on both growth plates on each vertebra, the growth rate on the convex side was almost null while it was typically maintained to a rate of 0.48-0.66 mm/year (0.8-1.1 mm year reduced by 40% because of an increased compression of 0.2 MPa) on the concave side.”