Monthly Archives: February 2012


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.”