Purpose of Review
We outline the diverse processes contributing to bone mineralization and bone matrix maturation by describing two mouse models with bone strength defects caused by restricted ...deletion of the receptor tyrosine kinase ligand EphrinB2.
Recent Findings
Stage-specific EphrinB2 deletion differs in its effects on skeletal strength. Early-stage deletion in osteoblasts leads to osteoblast apoptosis, delayed initiation of mineralization, and increased bone flexibility. Deletion later in the lineage targeted to osteocytes leads to a brittle bone phenotype and increased osteocyte autophagy. In these latter mice, although mineralization is initiated normally, all processes involved in matrix maturation, including mineral accrual, carbonate substitution, and collagen compaction, progress more rapidly.
Summary
Osteoblasts and osteocytes control the many processes involved in bone mineralization; defining the contributing signaling activities may lead to new ways to understand and treat human skeletal fragilities.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Mineralized bone forms when collagen-containing osteoid accrues mineral crystals. This is initiated rapidly (primary mineralization), and continues slowly (secondary mineralization) until bone is ...remodeled. The interconnected osteocyte network within the bone matrix differentiates from bone-forming osteoblasts; although osteoblast differentiation requires EphrinB2, osteocytes retain its expression. Here we report brittle bones in mice with osteocyte-targeted EphrinB2 deletion. This is not caused by low bone mass, but by defective bone material. While osteoid mineralization is initiated at normal rate, mineral accrual is accelerated, indicating that EphrinB2 in osteocytes limits mineral accumulation. No known regulators of mineralization are modified in the brittle cortical bone but a cluster of autophagy-associated genes are dysregulated. EphrinB2-deficient osteocytes displayed more autophagosomes in vivo and in vitro, and EphrinB2-Fc treatment suppresses autophagy in a RhoA-ROCK dependent manner. We conclude that secondary mineralization involves EphrinB2-RhoA-limited autophagy in osteocytes, and disruption leads to a bone fragility independent of bone mass.
Despite the high frequency of HFE gene mutations in Western Europe, widespread screening for HFE hemochromatosis is not recommended due to its variable phenotype. Joint pain and a premature ...osteoarthritis-like disease including the hip joints are the most frequent manifestation in patients with HFE hemochromatosis and iron overload. Therefore, screening of patients with severe osteoarthritis of the hip could identify patients with HFE hemochromatosis.
In this prospective cross-sectional study, 940 patients aged <70 years with end-stage osteoarthritis of the hip undergoing elective joint replacement surgery were screened for HFE hemochromatosis and compared to age- and sex-matched controls.
No greater prevalence of C282Y homozygosity mutation or elevated serum ferritin or transferrin saturation levels was found in the study cohort with severe osteoarthritis of the hip than in controls from the general population.
Our screening approach could not identify an increased prevalence of HFE gene mutations and iron overload in younger patients with severe osteoarthritis of the hip.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by mutations or deletions in the dystrophin gene, for which there remains no cure. As DMD patients also develop bone ...fragility because of muscle weakness and immobilization, better understanding of the pathophysiological mechanisms of dystrophin deficiency will help develop therapies to improve musculoskeletal health. Since alterations in muscle phenotype can influence bone structure, we investigated whether modifying muscle contractile activity through low-frequency stimulation (LFS) could alter bone architecture in mouse models of DMD. We tested the hypothesis that increasing muscle contractile activity could influence bone mass and structure in dystrophin-deficient (
) and dystrophin- and utrophin-deficient (
) dystrophic mice. Tibial bone structure in
mice was significantly different from that in
and wild-type (C57BL/10) control mice. Effects of LFS on bone architecture differed between dystrophic and healthy mice, with LFS thinning cortical bone in both dystrophic models. Bone mass was maintained in LFS-treated healthy mice, with a reduced proportion of high-density bone and concomitant increase in low-density bone. LFS-treated
mice exhibited a net deficit in cortical thickness and reduced high-density bone but no equivalent increase in low-density bone. These alterations in bone structure and mineral density reduced mechanical strength in
and
mice. The findings reveal that muscle activity can regulate bone mass, structure, mineral accrual, and strength, especially in the context of dystrophin and/or utrophin deficiency. The results provide unique insights into the development of bone fragility in DMD and for devising interventions to improve musculoskeletal health.
Patients with Duchenne muscular dystrophy (DMD) develop bone fragility because of muscle weakness and immobilization. We investigated whether increasing muscle contractile activity through low-frequency stimulation (LFS) could alter bone architecture in dystrophin-deficient (
) or dystrophin- and utrophin-deficient (
) mouse models of DMD. Chronic LFS reduced tibial diaphysis cross sections in
and
mice, without affecting bone shape in healthy mice. LFS affected the distribution of bone mineral density across all phenotypes, with the magnitude of effect being dependent on disease severity.
Bone strength is partially determined during cortical bone consolidation, a process comprising coalescence of peripheral trabecular bone and its progressive mineralisation. Mice with genetic deletion ...of suppressor of cytokine signalling 3 (Socs3), an inhibitor of STAT3 signalling, exhibit delayed cortical bone consolidation, indicated by high cortical porosity, low mineral content, and low bone strength. Since leptin receptor (LepR) is expressed in the osteoblast lineage and is suppressed by SOCS3, we evaluated whether LepR deletion in osteocytes would rectify the Dmp1cre.Socs3fl/fl bone defect. First, we tested LepR deletion in osteocytes by generating Dmp1cre.LepRfl/fl mice and detected no significant bone phenotype. We then generated Dmp1cre.Socs3fl/fl.LepRfl/fl mice and compared them to Dmp1cre.Socs3fl/fl controls. Between 6 and 12 weeks of age, both Dmp1cre.Socs3fl/fl.LepRfl/fl and control (Dmp1cre.Socs3fl/fl) mice showed an increasing proportion of more heavily mineralised bone, indicating some cortical consolidation with time. However, at 12 weeks of age, rather than resolving the phenotype, delayed consolidation was extended in female Dmp1cre.Socs3fl/fl.LepRfl/fl mice. This was indicated in both metaphysis and diaphysis by greater proportions of low-density bone, lower proportions of high-density bone, and greater cortical porosity than Dmp1cre.Socs3fl/fl controls. There was also no change in the proportion of osteocytes staining positive for phospho-STAT3, suggesting the effect of LepR deletion in Dmp1cre.Socs3fl/fl mice is STAT3-independent. This identifies a new role for leptin signalling in bone which opposes our original hypothesis. Although LepR in osteocytes has no irreplaceable physiological role in normal bone maturation, when STAT3 is hyperactive, LepR in Dmp1Cre-expressing cells supports cortical consolidation.
The inherited brittle bone disease osteogenesis imperfecta (OI) is commonly caused by COL1A1 and COL1A2 mutations that disrupt the collagen I triple helix. This causes intracellular endoplasmic ...reticulum (ER) retention of the misfolded collagen and can result in a pathological ER stress response. A therapeutic approach to reduce this toxic mutant load could be to stimulate mutant collagen degradation by manipulating autophagy and/or ER‐associated degradation. Since carbamazepine (CBZ) both stimulates autophagy of misfolded collagen X and improves skeletal pathology in a metaphyseal chondrodysplasia model, we tested the effect of CBZ on bone structure and strength in 3‐week‐old male OI Col1a2 +/p.G610C and control mice. Treatment for 3 or 6 weeks with CBZ, at the dose effective in metaphyseal chondrodysplasia, provided no therapeutic benefit to Col1a2 +/p.G610C mouse bone structure, strength or composition, measured by micro‐computed tomography, three point bending tests and Fourier‐transform infrared microspectroscopy. In control mice, however, CBZ treatment for 6 weeks impaired femur growth and led to lower femoral cortical and trabecular bone mass. These data, showing the negative impact of CBZ treatment on the developing mouse bones, raise important issues which must be considered in any human clinical applications of CBZ in growing individuals.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
With the aim to explore the restriction fragment length polymorphism
(RFLP) to Dde I restriction enzyme, the proviral region from 5181 to
6624 nts of HTLV-I was amplified by PCR. The 1033 bp fragment
...containing the terminal 5' of gene pol and the surface domain of
envelope gene (gp46) was amplified from PBMC proviral DNA of 29 HTLV-I
seropositive individuals from several areas of southwest Colombia. The
restriction analysis performed with Dde I revealed the circulation of
three different Dde I RFLP patterns. Pattern I (900 and 125 bp) was
observed in 34.5% (10/29) of isolates. Pattern IIa (700, 205 and 125
bp) was detected in 51.7% (15/29) of individuals. Finally, pattern IIb
(550, 350 and 125 bp) included only 13.8% (4/29) of samples studied.
Pattern IIb was exclusively detected in Tumaco in contrast with
patterns I and IIa that exhibited a tendency to be distributed in the
inland areas of southwest. Taken together results showed the existence
of a divergent microevolutionary mechanism operating in endemic areas
for HTLV-I infection of southwest Colombia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Exposure biomarkers were measured in urine collected during pregnancy and boyhood.•Some prenatal exposures were associated with reduced odds of adrenarche and puberty.•Prenatal exposures were not ...associated with boyhood hormone levels.•Boyhood exposures were not associated with adrenarche or puberty.•Some boyhood exposures were associated with decreased testosterone levels.
Phthalates and BPA are known endocrine disruptors and exposure in pregnant mothers and children is ubiquitous. We explored the relationship of prenatal and childhood exposures with pubertal onset and sex hormones in boys (ages 8–14). Phthalate metabolites and BPA were measured in maternal 3rd trimester or childhood urine. Sex hormones DHEAS, estradiol, inhibin B, SHBG, and total testosterone were measured in serum. Adrenarche and puberty were assessed by pediatrician. Prenatal exposure to some phthalates was associated with decreased DHEAS and inhibin B levels, and with increased SHBG. Prenatal exposure to most phthalates and BPA was associated with greatly reduced odds of adrenarche (odds ratios OR=0.12–0.65) and slightly reduced odds of puberty (OR=0.50–0.98). Childhood exposure was not associated with adrenarche or puberty, but some phthalates and BPA were associated with increased SHBG levels and decreased total and free testosterone levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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