Véronique Breuil

Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and Reverses Osteoporosis

Osteoporosis constitutes a major worldwide public health burden characterized by enhanced skeletal fragility. Bone metabolism is the combination of bone resorption by osteoclasts and bone formation by osteoblasts. Whereas increase in bone resorption is considered as the main contributor of bone loss that may lead to osteoporosis, this loss is accompanied by increased bone marrow adiposity. Osteoblasts and adipocytes share the same precursor cell and an inverse relationship exists between the two lineages. Therefore, identifying signaling pathways that stimulate mesenchymal stem cells osteogenesis at the expense of adipogenesis is of major importance for developing new therapeutic treatments. For this purpose, we identified by transcriptomic analysis the oxytocin receptor pathway as a potential regulator of the osteoblast/adipocyte balance of human multipotent adipose‐derived stem (hMADS) cells. Both oxytocin (OT) and carbetocin (a stable OT analogue) negatively modulate adipogenesis while promoting osteogenesis in both hMADS cells and human bone marrow mesenchymal stromal cells. Consistent with these observations, ovariectomized (OVX) mice and rats, which become osteoporotic and exhibit disequilibrium of this balance, have significant decreased OT levels compared to sham‐operated controls. Subcutaneous OT injection reverses bone loss in OVX mice and reduces marrow adiposity. Clinically, plasma OT levels are significantly lower in postmenopausal women developing osteoporosis than in their healthy counterparts. Taken together, these results suggest that plasma OT levels represent a novel diagnostic marker for osteoporosis and that OT administration holds promise as a potential therapy for this disease.

Hip osteoarthritis: short-term efficacy and safety of viscosupplementation by hylan G-F 20. An open-label study in 22 patients

UNLABELLED We studied the short-term safety and efficacy of intraarticular hylan G-F 20 (Synvisc) in patients with symptomatic hip osteoarthritis. METHODS In this open-label prospective study, patients who had hip osteoarthritis with a visual analog pain scale score greaterthan 40/100 and a Lequesne index greater than 6 received one or two intra-articular injections of hylan G-F 20 under fluoroscopic guidance. The patients were evaluated once a month. A response was defined as a 50% decrease in the Lequesne score after 1 month as compared to baseline. RESULTS Thirty injections were performed in 22 patients with a mean age of 54 years. The response rate was 50% (11/22) after the first injection. Five of the 11 patients who failed to respond to the first injection received a second injection on day 30; two had a response, yielding a cumulative response rate of 13/22. In the six patients followed up for more than 6 months, the improvement was sustained. Short-term safety was satisfactory, with a self-limited exacerbation of pain during the first few days in three patients but no infections or other side effects.

Insufficiency fracture of the sacrum revealing a pregnancy associated osteoporosis. First case report

Osteoporosis of pregnancy, usually responsible for spinal or femoral fracture,1 is rare as is insufficiency fracture of the sacrum, usually occurring in the elderly.2Magnetic resonance imaging (MRI) permitted during pregnancy, led us to diagnose an insufficiency fracture of the sacrum revealing a pregnancy associated osteoporosis, never previously reported to the best of our knowledge. Rheumatologists need to be aware of this new cause of pelvic pain during pregnancy. A 29 year old pregnant (seventh month) woman presented with a spontaneous acute claudication in conjunction with a left hyperalgesic buttock pain. Her past medical history showed: low back pain, since the second month of her pregnancy, relieved by rest and paracetamol; smoking (10 packet years) stopped at the sixth month of pregnancy; one spontaneous miscarriage at six months responsible for …

Erdheim-Chester disease: typical radiological bone features for a rare xanthogranulomatosis

A 55 year old man was admitted to the rheumatology department owing to inflammatory back pain (occurring at 4 00 am, not aggravated by movement) without sciatica, increasingly severe over two years and associated with asthenia and weight loss (10 kg). No abnormalities were found on physical examination, except for tenderness on palpation of the spinous processes of L5 and S1. There was no significant past medical history. Laboratory tests showed a mild inflammatory picture: erythrocyte sedimentation rate 25 mm/1st h (normal 5–15), C reactive protein 12 mg/l (normal 0–10), fibrinogen 5.1 g/l (normal 2–4). Protein electrophoresis, red and white blood cell count, glucose, renal, and liver function tests were normal. Chemical bone markers (urinary pyridinoline, alkaline phosphatase, osteocalcin, parathormone, 25-hydroxyvitamin D, serum calcium and phosphorus, and urinary calcium and phosphorus) were normal. Standard lumbar spine and pelvic radiographs were normal. Technetium-99m bone scintigraphy showed no abnormal uptake in the spine or skull but disclosed an increased peripheral uptake. A skeletal survey showed multiple mixed bone lesions with sclerotic areas surrounding smaller lytic foci. These roughly bilateral, symmetrical lesions involved the metaphyses and diaphyses of some long bones but spared the epiphyses. Bones affected were the femora, tibiae, radii, wrist, and tarsal bones (fig 1). Figure 1 Skeletal bone radiographs showed bilateral and symmetrical cortical osteosclerosis of the …

The receptor activator of nuclear factor (NF)-κB ligand (RANKL) is a new chemotactic factor for human monocytes

Bone resorption is regulated by the immune system, where receptor activator of nuclear factor (NF)κB ligand (RANKL), a new member of the tumor‐necrosis factor family, may contribute to pathological conditions. Due to the role of RANKL in the maturation of monocyte‐derived osteoclasts, we hypothesized that RANKL could exert chemotactic properties toward monocytic cells. Our results demonstrate that RANKL induces the migration of MonoMac‐6 monocytic cells as well as human freshly isolated total peripheral blood mononuclear cells (PBMC) and CD14+ purified PBMC. RANKL induces the migration of MonoMac‐6 cells in a dose‐dependent manner and with an efficacy similar to MCP‐1. After an 8‐h incubation, the soluble form of RANKL (sRANKL) started to exhibit a chemoattractive effect on MonoMac‐6 cells, with an increased effect observed up to 24 h. RANKL elicits an additive chemotactic effect to MCP‐1. Furthermore, addition of the RANKL decoy receptor osteoprotegerin in the lower well or RANKL in the upper well abrogates the RANKL‐induced migration of MonoMac‐6 cells, hallmarking a true specific activity. RNase protection assay experiments indicate that exposure of MonoMac‐6 cells to RANKL had no significant effect on the expression of a variety of chemokines, known to attract monocytes. This study provides evidence that RANKL behaves as a chemotactic factor for monocytic cells, emphazing the cross‐talk between bone and immune systems.

Gonadal dysgenesis and bone metabolism.

Gonadal dysgenesis is defined as congenital hypogonadism related to abnormalities of the sex chromosomes. Because sex steroids play a central role in the acquisition and maintenance of bone mass, studies have been done to investigate bone status in patients with gonadal dysgenesis, particularly Turners syndrome and Klinefelters syndrome, which are the two most common types. The severe estrogen deficiency characteristic of Turners syndrome (44, X0) is associated with a significant bone mass decrease ascribable to increased bone turnover, as shown by histological studies and assays of bone turnover markers. Estrogen therapy is followed by a significant bone mass gain and a return to normal of bone turnover markers, suggesting that it is the estrogen deficiency rather than the chromosomal abnormality that causes the bone mass deficiency, although abnormalities in the renal metabolism of vitamin D have been reported. Combined therapy with estrogens and growth hormone seems beneficial during the prepubertal period. In Klinefelters syndrome (47XXY), serum testosterone levels are at the lower end of the normal range and dihydrotestosterone levels are low. Histological studies show depressed osteoblast function and a decrease in 5-alpha-reductase activity responsible for partial tissue resistance to androgens. Assays of bone turnover markers show evidence of increased bone turnover. The bone deficiency is most marked at the femoral neck and seems correlated with serum testosterone and estradiol levels. Androgen therapy has favorable effects on the bone only if it is started before puberty. Recent data suggest that estrogens may contribute to the development of demineralization in KS and that bisphosphonate therapy may be beneficial.

Occipitocervical Fixation Using Hooks and Screws for Upper Cervical Instability

OBJECTIVES Occipitocervical fixation is used for the treatment of nontraumatic upper cervical instabilities. To date, plates have been fixed with screws or wires. However, these devices are not indicated in the treatment of patients with severe osteoporosis or in instances of significant thinning of the occipital bone. We performed a clinical trial of a new type of fixation that uses cervical interlaminar hooks and occipital claws with hooks or with screws (CCD type; Sofamor-Danek, Roissy, France) for the treatment of nontraumatic upper cervical instabilities. METHODS Five women and one man ranging in age from 28 to 72 years (average age, 54 yr) were thus treated. The CCD type material had two rod plates and hooks allowing the proper placement of interlaminar and occipital claws. The occipital plate can also be directly screwed to the bone. Occipital hooks were used in four patients. The other two patients, who had occipitocervical congenital abnormalities that required an occipitocervical opening and an additional dural enlargement, underwent occipital screw fixation because of the previous opening of the foramen magnum. A cancellous iliac autograft allowed the usual fusion. RESULTS No postoperative complications were observed, and all patients experienced significant improvement of their neck pain. Four patients had neurological symptoms. The condition of two patients improved, and the condition of the other two stabilized. CONCLUSION This report confirms the interest of the CCD method to correct all types of upper cervical instabilities, even in cases of unusual thinning of the occipital bone or in osteoporotic states.

Oxytocin and bone remodelling: Relationships with neuropituitary hormones, bone status and body composition

PURPOSE There is growing evidence that oxytocin, which regulates appetite, plays a role in bone remodelling and improves osteoporosis. We previously showed a significant decrease in circulating oxytocin levels in postmenopausal osteoporotic women compared to healthy controls. However, factors involved in the pathophysiology of osteoporosis, such as estrogens and leptin, are known to regulate oxytocin secretion. Herein, we evaluated the relationships between oxytocin and other hormonal factors known to regulate bone remodeling and body composition in postmenopausal osteoporotic women, compared to healthy controls. METHODS In 20 postmenopausal women with severe osteoporosis compared to 16 healthy controls, we measured serum levels of oxytocin, high sensitive estradiol, testosterone, FSH, LH, SHBG, TSH, osteocalcin, serum type I collagen carboxy-terminal telopeptide, leptin. Bone mineral density and body composition were also measured with DXA. RESULTS Osteoporotic women had significantly lower oxytocin, leptin and LH serum levels and higher CTX and SHBG; all other biological parameters were similar in both groups. Fat mass and lean mass were significantly decreased in osteoporotic women. Oxytocin serum levels were significantly correlated to bone mineral density but not to any other measured parameter, including leptin, estradiol and age. In a logistic regression analysis, osteoporosis remained significantly correlated to oxytocin, regardless of age. CONCLUSIONS Low oxytocin serum levels appeared to be associated with severe osteoporosis, independently of other factors associated with osteoporosis or known to regulate oxytocin serum levels, such as estradiol or leptin, reinforcing the concept that oxytocin may be involved in the pathophysiology of postmenopausal osteoporosis.

Trabecular Bone Score: Where are we now?

The Trabecular Bone Score is a rather new index obtained at the lumbar spine at the same time as a real bone mineral density. It was developed to reflect bone microarchitecture. It was proposed to be easily used in everyday practice as a surrogate of bone strength. Our aim was to review 1. technical points such as correlations between Trabecular Bone Score and bone microarchitectural parameters, Trabecular Bone Score and bone strength, the effects of dual-energy X-ray absorptiometry image spatial resolution, age, macroarchitecture, body mass index, and osteoarthritis, on Trabecular Bone Score, and 2. evidences to use Trabecular Bone Score for separating individuals with fragility fractures from controls, predicting fragility fractures, and for longitudinally monitoring changes related to treatments. Correlations between Trabecular Bone Score and bone microarchitectural parameters vary widely across bone sites, microarchitectural parameters, and study designs. In vivo, the Trabecular Bone Score explains little of the variance in trabecular microarchitectural parameters. We emphasize that it is a texture parameter. The Trabecular Bone Score is reduced in patients with fragility fracture. Several retrospective and prospective studies have shown its discriminative ability regarding the fracture risk. When combining the areal Bone mineral Density and Trabecular Bone Score, the Trabecular Bone Score remains a predictor of fracture but not the areal Bone Mineral Density. However in prospective studies, the best predictor of fracture remains hip areal bone mineral density. Due to the lack of evidence, we recommend not to use Trabecular Bone Score for following patients treated by anti-osteoporotic drugs.

Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids

Extracellular pH variations are seen as the principal endogenous signal that triggers activation of Acid‐Sensing Ion Channels (ASICs), which are basically considered as proton sensors, and are involved in various processes associated with tissue acidification. Here, we show that human painful inflammatory exudates, displaying non‐acidic pH, induce a slow constitutive activation of human ASIC3 channels. This effect is largely driven by lipids, and we identify lysophosphatidylcholine (LPC) and arachidonic acid (AA) as endogenous activators of ASIC3 in the absence of any extracellular acidification. The combination of LPC and AA evokes robust depolarizing current in DRG neurons at physiological pH 7.4, increases nociceptive C‐fiber firing, and induces pain behavior in rats, effects that are all prevented by ASIC3 blockers. Lipid‐induced pain is also significantly reduced in ASIC3 knockout mice. These findings open new perspectives on the roles of ASIC3 in the absence of tissue pH variation, as well as on the contribution of those channels to lipid‐mediated signaling.