Publications by authors named "Anna Spagnoli"

46 Publications

A randomised placebo-controlled clinical trial on the efficacy of local lidocaine injections and oral citalopram for the treatment of complex regional pain syndrome.

J Plast Reconstr Aesthet Surg 2021 Nov 14. Epub 2021 Nov 14.

"Sapienza" University of Rome, Department of Plastic and Reconstructive Surgery, Rome, Italy.

Background: Complex regional pain syndrome (CRPS) is a neuropathic pain condition with no universally recognised treatment. The study evaluates the efficacy of a therapeutic protocol consisting of oral citalopram and lidocaine injections in patients affected by CRPS.

Methods: Between January 2010 and December 2014, 150 consecutive patients with CRPS were enrolled in the study and randomly assigned into three groups: group one - lidocaine injection and oral citalopram; group two - lidocaine injection and oral placebo; and group three - injective and oral placebo. The Impairment Sum Score (ISS) was used to assess the severity of CRPS before, as well as at regular intervals after treatment commenced. Statistical significance (p < 0.05) was determined by paired t-tests.

Results: The combined treatment proved to be more effective (ISS 47.6 to 12.6) than local anaesthetic alone (ISS 47.5 to 21.5) and to placebo (ISS 47.2 to 29.9).

Conclusion: This study indicates that CRPS may be managed with well-tolerated association of oral citalopram and lidocaine injections.
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http://dx.doi.org/10.1016/j.bjps.2021.11.022DOI Listing
November 2021

Roux-en-Y gastric bypass decreases serum inflammatory markers and cardiovascular risk factors in obese diabetics.

Surgery 2021 03 7;169(3):539-542. Epub 2020 Nov 7.

Department of Surgery, Rush University Medical Center, Chicago, IL. Electronic address:

Background: Obesity and type 2 diabetes mellitus are associated with elevated levels of inflammatory markers. This chronic inflammation is known to contribute to increased risk of cardiovascular disease in these populations. Laparoscopic Roux-en-Y gastric bypass is associated with a high rate of diabetes remission. We hypothesize that laparoscopic Roux-en-Y gastric bypass decreases systemic inflammatory markers and cardiovascular disease risk factors in obese diabetics.

Methods: This was a single-institution prospective cohort study of 61 obese patients with type 2 diabetes mellitus. A total of 30 patients underwent laparoscopic Roux-en-Y gastric bypass surgery, and 31 patients underwent standard medical therapy with diabetes support and education. Collected data included preoperative and postoperative inflammatory biomarkers and clinical parameters.

Results: Twelve months after undergoing laparoscopic Roux-en-Y gastric bypass, controlling for sex and age, there was a significant correlation between a change in interleukin-6 and a change in systolic blood pressure (Spearman r = 0.41, P = .03). Similarly, when sex and age were controlled for in the laparoscopic Roux-en-Y gastric bypass group, a statistically significant relationship remained between percent excess weight loss and change in interleukin-6 (P = .001).

Conclusion: A significant relationship exists between decreased systemic interleukin-6 levels and both excess weight loss and lowered systolic blood pressure after laparoscopic Roux-en-Y gastric bypass in obese patients with diabetes mellitus. These correlations may explain the decreased risk of cardiovascular disease after surgical weight reduction in this patient population.
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http://dx.doi.org/10.1016/j.surg.2020.09.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870514PMC
March 2021

Role of Prx1-expressing skeletal cells and Prx1-expression in fracture repair.

Bone 2020 10 3;139:115521. Epub 2020 Jul 3.

Department of Orthopaedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, IL, USA; Department of Pediatrics, Division of Pediatric Endocrinology, Rush University Medical Center, Chicago, IL, USA. Electronic address:

The healing capacity of bones after fracture implies the existence of adult regenerative cells. However, information on identification and functional role of fracture-induced progenitors is still lacking. Paired-related homeobox 1 (Prx1) is expressed during skeletogenesis. We hypothesize that fracture recapitulates Prx1's expression, and Prx1 expressing cells are critical to induce repair. To address our hypothesis, we used a combination of in vivo and in vitro approaches, short and long-term cell tracking analyses of progenies and actively expressing cells, cell ablation studies, and rodent animal models for normal and defective fracture healing. We found that fracture elicits a periosteal and endosteal response of perivascular Prx1+ cells that participate in fracture healing and showed that Prx1-expressing cells have a functional role in the repair process. While Prx1-derived cells contribute to the callus, Prx1's expression decreases concurrently with differentiation into cartilaginous and bone cells, similarly to when Prx1+ cells are cultured in differentiating conditions. We determined that bone morphogenic protein 2 (BMP2), through C-X-C motif-ligand-12 (CXCL12) signaling, modulates the downregulation of Prx1. We demonstrated that fracture elicits an early increase in BMP2 expression, followed by a decrease in CXCL12 that in turn down-regulates Prx1, allowing cells to commit to osteochondrogenesis. In vivo and in vitro treatment with CXCR4 antagonist AMD3100 restored Prx1 expression by modulating the BMP2-CXCL12 axis. Our studies represent a shift in the current research that has primarily focused on the identification of markers for postnatal skeletal progenitors, and instead we characterized the function of a specific population (Prx1+ cells) and their expression marker (Prx1) as a crossroad in fracture repair. The identification of fracture-induced perivascular Prx1+ cells and regulation of Prx1's expression by BMP2 and in turn by CXCL12 in the orchestration of fracture repair, highlights a pathway in which to investigate defective mechanisms and therapeutic targets for fracture non-union.
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http://dx.doi.org/10.1016/j.bone.2020.115521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484205PMC
October 2020

Association of Bariatric Surgery With Risk of Fracture in Patients With Severe Obesity.

JAMA Netw Open 2020 06 1;3(6):e207419. Epub 2020 Jun 1.

Department of Surgery, Rush University Medical Center, Chicago, Illinois.

Importance: Given the complex relationship between body mass index, body composition, and bone density and the correlative nature of the studies that have established the prevailing notion that higher body mass indices may be protective against osteopenia and osteoporosis and, therefore, fracture, the absolute risk of fracture in patients with severe obesity who undergo either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) compared with those who do not undergo bariatric surgery is unknown.

Objective: To assess the rates of fractures associated with obesity and compare rates between those who do not undergo bariatric surgery, those who undergo RYGB, and those who undergo SG.

Design, Setting, And Participants: In this retrospective multicenter cohort study of Medicare Standard Analytic Files derived from Medicare parts A and B records from January 2004 to December 2014, patients classified as eligible for bariatric surgery using the US Centers of Medicare & Medicaid criteria who either did not undergo bariatric surgery or underwent RYGB or SG were exactly matched in a 1:1 fashion based on their age, sex, Elixhauser Comorbidity Index, hypertension, smoking status, nonalcoholic fatty liver disease, hyperlipidemia, type 2 diabetes, osteoporosis, osteoarthritis, and obstructive sleep apnea status. Data were analyzed from November to December 2019.

Exposures: RYGB or SG.

Main Outcomes And Measures: The primary outcome measured in this study was the odds of fracture overall based on exposure to bariatric surgery. Secondary outcomes included the odds of type of fracture (humerus, radius or ulna, pelvis, hip, vertebrae, and total fractures) based on exposure to bariatric surgery.

Results: A total of 49 113 patients were included and were equally made up of 16 371 bariatric surgery-eligible patients who did not undergo weight loss surgery, 16 371 patients who had undergone RYGB, and 16 371 patients who had undergone SG. Each group consisted of an equal number of 4109 men (25.1%) and 12 262 women (74.9%) and had an equal distribution of ages, with 11 780 patients (72.0%) 64 years or younger, 4230 (25.8%) aged 65 to 69 years, 346 (2.1%) aged 70 to 74 years, and 15 (0.1%) aged 75 to 79 years. Patients undergoing RYGB were found to have no significant difference in odds of fractures compared with bariatric surgery-eligible patients who did not undergo surgery. Patients undergoing undergone SG were found to have decreased odds of fractures of the humerus (odds ratio [OR], 0.57; 95% CI, 0.45-0.73), radius or ulna (OR, 0.38; 95% CI, 0.25-0.58), hip (OR, 0.49; 95% CI, 0.33-0.74), pelvis (OR, 0.34; 95% CI, 0.18-0.64), vertebrae (OR, 0.60; 95% CI, 0.48-0.74), or fractures in general (OR, 0.53; 95% CI, 0.46-0.62). Compared with patients undergoing SG, patients undergoing RYGB had a significantly greater risk of total fractures (OR, 1.79; 95% CI, 1.55-2.06) and humeral fractures (OR, 1.60; 95% CI, 1.24-2.07).

Conclusions And Relevance: In this cohort study, bariatric surgery was associated with a reduced risk of fracture in bariatric surgery-eligible patients. Sleeve gastrectomy might be the best option for weight loss in patients in which fractures could be a concern, as RYGB may be associated with an increased fracture risk compared with SG.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.7419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287567PMC
June 2020

Perioperative changes in prouroguanylin hormone response in severely obese subjects after bariatric surgery.

Surgery 2019 10 29;166(4):456-459. Epub 2019 Aug 29.

Department of Pediatrics, University of Nebraska Medical Center, Omaha.

Background: Prouroguanylin is a gut hormone converted into uroguanylin in the hypothalamus. Uroguanylin induces satiety through guanylyl-cyclase-2C receptor signaling. However, little is known about the role of this hormone in regulating human food intake.

Methods: In prospective-cohort study, prouroguanylin profile changes were determined during meal stimulation in obese patients 2 weeks before and 2 weeks after Roux-en-Y gastric bypass surgery. We also investigated whether these changes play a role in the anorexigenic effect of Roux-en-Y gastric bypass.

Results: The study enrolled 8 healthy lean volunteers and 10 obese patients with type 2 diabetes. Prouroguanylin levels were postprandially decreased at 30 minutes (P = .04) and 60 minutes (P = .008) in obese patients before surgery, and they were increased at 60 minutes (P = .003), 90 minutes (P = .008), and 120 minutes (P = .009) after surgery. We observed a significant difference (P = .001) in fasting prouroguanylin levels before (8.82 ± 1.2 ng/mL) and after (6.05 ± 1.2 ng/mL) Roux-en-Y gastric bypass. Hunger ratings in the fasted state did not change after Roux-en-Y gastric bypass. Instead, subjects demonstrated significantly (P = .01) lower hunger visual analog scale scores than before Roux-en-Y gastric bypass. No correlations between circulating prouroguanylin levels and hunger perception were found before or after Roux-en-Y gastric bypass.

Conclusion: Prouroguanylin levels decrease after meal stimulation in obese patients, and they increase after Roux-en-Y gastric bypass, but no correlations exist with hunger visual analog scale scores.
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http://dx.doi.org/10.1016/j.surg.2019.06.037DOI Listing
October 2019

Effects of Roux-en-Y Gastric Bypass on Osteoclast Activity and Bone Density in Morbidly Obese Patients with Type 2 Diabetes.

Obes Surg 2020 01;30(1):290-295

Department of Surgery, Rush University Medical Center, 1750 W Harrison St, 791 Jelke, Chicago, IL, 60612, USA.

Introduction: Roux-en-Y gastric bypass (RYGB) is a well-established treatment for morbid obesity and type 2 diabetes. The effects of RYGB on bone metabolism and bone health are largely unknown.

Objective: Determine the changes in osteoclast function and bone density 1 year after RYGB as compared with a control group undergoing a diabetes support and education program (DSE).

Design: A prospective cohort study with patients matched for weight and age assigned to RYGB or DSE.

Setting: Large academic institution.

Patients Or Other Participants: Patients with type 2 diabetes mellitus and morbid obesity (body mass index greater than 35 kg/m).

Intervention: Subjects either received laparoscopic RYBG or DSE, which consisted of nutritional, exercise, and dietary counseling performed by a certified diabetic educator and a nutritionist three times over a year.

Main Outcome Measure: Osteoclast activity, bone mineral density.

Results: One year after, intervention subjects undergoing RYGB have a 280% increase in osteoclast activity as compared with a 7.6% increase in the DSE control group (P < 0.001). Furthermore, there was a statistically significant increase in sclerostin levels in subjects undergoing RYGB compared with an increase in the control group. The total bone mineral density was statistically unchanged within 1 year of intervention in both groups. A statistically significant decrease in bone mineral density in the left ribs (decrease of 6.8%, P < 0.05) and lumbar spine (decrease of 4.0%, P < 0.05) was seen 1 year after RYGB.

Conclusions: There is a significant increase in osteoclast activity observed 1 year after RYGB; the long-term clinical implications of this increased bone metabolism are unknown.
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http://dx.doi.org/10.1007/s11695-019-04154-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515205PMC
January 2020

Tissue engineering a tendon-bone junction with biodegradable braided scaffolds.

Biomater Res 2019 16;23:11. Epub 2019 May 16.

5Department of Pediatrics, University of Nebraska Medical Center, Children's Hospital & Medical Center, Omaha, NE 68198-5945 USA.

Background: Tendons play an important role in transferring stress between muscles and bones and in maintaining the stability of joints. Tendon tears are difficult to heal and are associated with high recurrence rates. So, the objective of this study was to develop a biodegradable scaffold for tendon-bone junction regeneration.

Methods: Two types of polylactic acid (PLA) yarns, having fibers with round and four deep grooved cross-sections, were braided into tubular scaffolds and cultured with murine Transforming growth factor beta type II receptor (Tgfbr2)-expressing joint progenitor cells. The scaffolds were designed to mimic the mechanical, immuno-chemical and biological properties of natural mouse tendon-bone junctions. Three different tubular scaffolds measuring 2 mm in diameter were braided on a Steeger 16-spindle braiding machine and biological and mechanical performance of the three scaffolds were evaluated.

Results: The mechanical test results indicated that three different braided scaffold structures provided a wide range of mechanical properties that mimic the components of tendon bone junction and results of the biological tests confirmed cell viability, active cell attachment and proliferation throughout all three scaffolds.

Conclusions: This study has identified that the three proposed types of braided scaffolds with some improvement in their structures have the potential to be used as scaffolds for the regeneration of a tendon bone tissue junction.
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http://dx.doi.org/10.1186/s40824-019-0160-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521458PMC
May 2019

TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis.

Sci Transl Med 2019 05;11(491)

Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA.

Mechanisms that govern the shift from joint homeostasis to osteoarthritis (OA) remain unknown. Here, we identify a pathway used for joint development and homeostasis, and its role in OA. Using a combination of transgenic, pharmacological, and surgical conditions in mouse and human tissues, we found that TGF-β signaling promotes joint homeostasis through regulation of the IL-36 family. We identified IL-36 receptor antagonist (IL-36 in mice and IL-36RN in humans) as a potential disease-modifying OA drug. Specifically, OA development was associated with IL-36α up-regulation and IL-36Ra down-regulation in mice with tissue-specific postnatally induced ablation of , mice treated with a TGF-β signaling inhibitor, mice with posttraumatic OA, and aging mice with naturally occurring OA. In human cartilage, OA severity was associated with decreased TGFBR2 and IL-36RN, whereas IL-36α increased. Functionally, intra-articular treatment with IL-36Ra attenuated OA development in mice, and IL-36RN reduced MMP13 in human OA chondrocytes. These findings highlight the relevance of TGFBR2-IL-36 interplay in joint homeostasis and IL-36RN as a potential therapeutic agent for OA.
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http://dx.doi.org/10.1126/scitranslmed.aan2585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102613PMC
May 2019

Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging.

Ann N Y Acad Sci 2019 04 12;1442(1):48-60. Epub 2018 Aug 12.

Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois.

Over the last two decades, it has become increasingly apparent that Wnt signaling plays a critical role in development and adult tissue homeostasis in multiple organs and in the pathogenesis of many diseases. In particular, a crucial role for Wnt signaling in bone development and bone tissue homeostasis has been well recognized. Numerous genome-wide association studies confirmed the importance of Wnt signaling in controlling bone mass. Moreover, ample evidence suggests that Wnt signaling is essential for kidney, intestine, and adipose tissue development and homeostasis. Recent emerging evidence demonstrates that Wnt signaling may play a fundamental role in the aging process of those organs. New discoveries show that bone is not only the major reservoir for calcium and phosphate storage, but also the largest organ with multiple functions, including mineral and energy metabolism. The interactions among bone, kidney, intestine, and adipose tissue are controlled and regulated by several endocrine signals, including FGF23, klotho, sclerostin, osteocalcin, vitamin D, and leptin. Since the aging process is characterized by structural and functional decline in almost all tissues and organs, understanding the Wnt signaling-related interactions among bone, kidney, intestine, and adipose tissue in aging may shed light on the pathogenesis of age-related diseases.
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http://dx.doi.org/10.1111/nyas.13945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372353PMC
April 2019

Bifid median nerve and carpal tunnel syndrome: an uncommon anatomical variation.

Ann Ital Chir 2017 ;88:95-96

Dear sir, one of the most common entrapment neuropathy syndromes in clinical practice is "Entrapment of median nerve in carpal tunnel" also called "Carpal tunnel syndrome (CTS)" (Aydin et al., 2007; Huisstede et al., 2010). This syndrome is caused by entrapment of the median nerve in the wrist (Preston and Shapiro, 2005) when the pressure increases in the carpal tunnel. A high division of the median nerve proximal to the carpal tunnel, also known as a bifid median nerve, is a rare anatomic variation that may be associated with CTS and with persistent median vessels (Lanz, 1977). This anatomic variation has an incidence of 0,8% to 2,3% in patients with CTS. Lanz (1977) has characterized this anatomic condition of the median nerve in the carpal tunnel. These anatomic variants have been classified into four groups: - Group 0: extraligamentous thenar branch (standard anatomy); - Group 1: variations of the course of the thenar branch; - Group 2: accessory branches at the distal portion of the carpal tunnel; - Group 3: divided or duplicated median nerve inside the carpal tunnel; - Group 4: accessory branches proximal to the carpal tunnel. During dissection of the wrist performed for the treatment of a CTS under local anesthesia, we found an anatomical variation of the median nerve that was divided in two branches inside the carpal tunnel (Group 3 of Lanz Classification) and in which its radial branch passed through its own compartment. The two parts of the nerve seems to be unequal in size (Fig. 1). Moreover the nerve passed in carpal tunnel associated with a median artery, so we classified this variation in the group 3b of Lanz Classification (Fig. 2). The persistence of median artery coexisting with a bifid median nerve has been widely reported in surgical literature (Lanz, 1977; Barbe et al., 2005). Before surgical intervention clinical evaluation of patient and electrophysiological examination showed no differences compared to a non bifid median nerve entrapment syndrome. In conclusion the bifid median nerve may facilitate compression of median nerve in the carpal tunnel because of its increased cross sectional area even if it has no electrophysiological or clinical differential diagnosis in case of CTS. The aim of this letter is aware the physicians in order to borne in mind the possible presence of a median nerve variation during dissection of carpal tunnel in order to avoid the damage of this non common anatomical structures.
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April 2018

Extracorporeal Shock Wave Therapy: An Emerging Treatment Modality for Retracting Scars of the Hands.

Ultrasound Med Biol 2016 Jan 9;42(1):185-95. Epub 2015 Oct 9.

Department of Plastic and Reconstructive Surgery, "Sapienza" University, Policlinico Umberto I, Rome, Italy.

Prolonged and abnormal scarring after trauma, burns and surgical procedures often results in a pathologic scar. We evaluated the efficacy of unfocused shock wave treatment, alone or in combination with manual therapy, on retracting scars on the hands. Scar appearance was assessed by means of the modified Vancouver Scar Scale; functional hand mobility was evaluated using a range-of-motion scale, whereas a visual analogue score was implemented for detecting any improvements in referred pain. Additionally, biopsy specimens were collected for clinico-pathologic correlation. For each active treatment group, statistically significant improvements in modified Vancouver Scar Scale were recorded as early as five treatment sessions and confirmed 2 wk after the last treatment session. Analogous results were observed when assessing pain and range of movement. Histopathological examination revealed significant increases in dermal fibroblasts in each active treatment group, as well as in neoangiogenetic response and type-I collagen concentration.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2015.07.028DOI Listing
January 2016

BMP2 Regulation of CXCL12 Cellular, Temporal, and Spatial Expression is Essential During Fracture Repair.

J Bone Miner Res 2015 Nov 15;30(11):2014-27. Epub 2015 Jun 15.

Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

The cellular and humoral responses that orchestrate fracture healing are still elusive. Here we report that bone morphogenic protein 2 (BMP2)-dependent fracture healing occurs through a tight control of chemokine C-X-C motif-ligand-12 (CXCL12) cellular, spatial, and temporal expression. We found that the fracture repair process elicited an early site-specific response of CXCL12(+)-BMP2(+) endosteal cells and osteocytes that was not present in unfractured bones and gradually decreased as healing progressed. Absence of a full complement of BMP2 in mesenchyme osteoprogenitors (BMP2(cKO/+)) prevented healing and led to a dysregulated temporal and cellular upregulation of CXCL12 expression associated with a deranged angiogenic response. Healing was rescued when BMP2(cKO/+) mice were systemically treated with AMD3100, an antagonist of CXCR4 and agonist for CXCR7 both receptors for CXCL12. We further found that mesenchymal stromal cells (MSCs), capable of delivering BMP2 at the endosteal site, restored fracture healing when transplanted into BMP2(cKO/+) mice by rectifying the CXCL12 expression pattern. Our in vitro studies showed that in isolated endosteal cells, BMP2, while inducing osteoblastic differentiation, stimulated expression of pericyte markers that was coupled with a decrease in CXCL12. Furthermore, in isolated BMP2(cKO/cKO) endosteal cells, high expression levels of CXCL12 inhibited osteoblastic differentiation that was restored by AMD3100 treatment or coculture with BMP2-expressing MSCs that led to an upregulation of pericyte markers while decreasing platelet endothelial cell adhesion molecule (PECAM). Taken together, our studies show that following fracture, a CXCL12(+)-BMP2(+) perivascular cell population is recruited along the endosteum, then a timely increase of BMP2 leads to downregulation of CXCL12 that is essential to determine the fate of the CXCL12(+)-BMP2(+) to osteogenesis while departing their supportive role to angiogenesis. Our findings have far-reaching implications for understanding mechanisms regulating the selective recruitment of distinct cells into the repairing niches and the development of novel pharmacological (by targeting BMP2/CXCL12) and cellular (MSCs, endosteal cells) interventions to promote fracture healing.
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http://dx.doi.org/10.1002/jbmr.2548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970512PMC
November 2015

Synovial joints: from development to homeostasis.

Curr Osteoporos Rep 2015 Feb;13(1):41-51

Department of Pediatrics, University of North Carolina at Chapel Hill, 109 Mason Farm Road, Chapel Hill, NC, 27599-7039, USA,

Synovial joint morphogenesis occurs through the condensation of mesenchymal cells into a non-cartilaginous region known as the interzone and the specification of progenitor cells that commit to the articular fate. Although several signaling molecules are expressed by the interzone, the mechanism is poorly understood. For treatments of cartilage injuries, it is critical to discover the presence of joint progenitor cells in adult tissues and their expression gene pattern. Potential stem cell niches have been found in different joint regions, such as the surface zone of articular cartilage, synovium, and groove of Ranvier. Inherited joint malformations as well as joint-degenerating conditions are often associated with other skeletal defects and may be seen as the failure of morphogenic factors to establish the correct microenvironment in cartilage and bone. Therefore, exploring how joints form can help us understand how cartilage and bone are damaged and develop drugs to reactivate this developing mechanism.
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http://dx.doi.org/10.1007/s11914-014-0247-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306636PMC
February 2015

Are HDL levels lower in children with type 1 diabetes and concurrent celiac disease compared with children with type 1 diabetes only?

J Pediatr Endocrinol Metab 2014 Nov;27(11-12):1213-6

Celiac disease (CD) is associated with type 1 diabetes mellitus (T1DM), which is known to be associated with abnormal lipid profiles. We aimed to examine the impact of CD on lipid profiles in persons with T1DM. Subjects with T1DM were identified by database and medical record review. Patients were classified as T1DM+CD or T1DM based on CD antibody and endoscopy results. The most recent (before age 20 years) non-fasting lipid panel (NFLP) prior to CD diagnosis for T1DM+CD subjects was compared to the most recent NFLP for T1DM subjects. Adjusted analysis showed T1DM+CD had lower HDL compared with T1DM (T1DM+CD 51.4 mg/dL, T1DM 62.2 mg/dL, p=0.017). There were no other differences in NFLP. In our sample, patients with T1DM+CD had lower HDL levels. Considering the increased cardiovascular disease risk of patients with T1DM, those who also have CD may be at even greater risk due to the association with lower HDL.
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http://dx.doi.org/10.1515/jpem-2013-0464DOI Listing
November 2014

Expression levels of insulin receptor substrate-1 modulate the osteoblastic differentiation of mesenchymal stem cells and osteosarcoma cells.

Growth Factors 2014 Feb 20;32(1):41-52. Epub 2014 Jan 20.

Laboratory of Experimental Oncology, CRS Development of Molecular Therapies, Orthopaedic Rizzoli Institute , Bologna , Italy .

The insulin-like growth factor-1 system, including its critical mediator insulin receptor substrate-1 (IRS-1), is involved in regulating osteosarcoma (OS) cell proliferation or differentiation. The aim of this study is to define the role of IRS-1 in OS cells by assessing the contribution of IRS-1 in the differentiation of human and murine OS cell lines and mouse mesenchymal stem cells (MSCs) and found that the basal level of IRS-1 is important for the initiation of differentiation. Both down-regulation and over-expression of IRS-1 inhibited osteoblastic differentiation. In vivo studies showed that OS cells over-expressing IRS-1 have increased metastatic potential and tumor growth. The proteasome inhibitor MG-132 led to an increase in IRS-1 protein level that inhibited osteoblastic differentiation, suggesting a role for proteasomal regulation in maintaining the appropriate expression level of IRS-1. Thus, precise regulation of IRS-1 expression level is critical for determining the differentiating capacity of MSCs and OS cells, and that derangement of IRS-1 levels can be a critical step in OS transformation.
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http://dx.doi.org/10.3109/08977194.2013.870168DOI Listing
February 2014

Joint TGF-β type II receptor-expressing cells: ontogeny and characterization as joint progenitors.

Stem Cells Dev 2013 May 15;22(9):1342-59. Epub 2013 Feb 15.

Department of Pediatrics, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599-7039, USA.

TGF-β type II receptor (Tgfbr2) signaling plays an essential role in joint-element development. The Tgfbr2(PRX-1KO) mouse, in which the Tgfbr2 is conditionally inactivated in developing limbs, lacks interphalangeal joints and tendons. In this study, we used the Tgfbr2-β-Gal-GFP-BAC mouse as a LacZ/green fluorescent protein (GFP)-based read-out to determine: the spatial and temporally regulated expression pattern of Tgfbr2-expressing cells within joint elements; their expression profile; and their slow-cycling labeling with bromodeoxyuridine (BrdU). Tgfbr2-β-Gal activity was first detected at embryonic day (E) 13.5 within the interphalangeal joint interzone. By E16.5, and throughout adulthood, Tgfbr2-expressing cells clustered in a contiguous niche that comprises the groove of Ranvier and the synovio-entheseal complex including part of the perichondrium, the synovium, the articular cartilage superficial layer, and the tendon's entheses. Tgfbr2-expressing cells were found in the synovio-entheseal complex niche with similar temporal pattern in the knee, where they were also detected in meniscal surface, ligaments, and the synovial lining of the infrapatellar fat pad. Tgfbr2-β-Gal-positive cells were positive for phospho-Smad2, signifying that the Tgfbr2 reporter was accurate. Developmental-stage studies showed that Tgfbr2 expression was in synchrony with expression of joint-morphogenic genes such as Noggin, GDF5, Notch1, and Jagged1. Prenatal and postnatal BrdU-incorporation studies showed that within this synovio-entheseal-articular-cartilage niche most of the Tgfbr2-expressing cells labeled as slow-proliferating cells, namely, stem/progenitor cells. Tgfbr2-positive cells, isolated from embryonic limb mesenchyme, expressed joint progenitor markers in a time- and TGF-β-dependent manner. Our studies provide evidence that joint Tgfbr2-expressing cells have anatomical, ontogenic, slow-cycling trait and in-vivo and ex-vivo expression profiles of progenitor joint cells.
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http://dx.doi.org/10.1089/scd.2012.0207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629851PMC
May 2013

TGF-β type II receptor/MCP-5 axis: at the crossroad between joint and growth plate development.

Dev Cell 2012 Jul;23(1):71-81

Department of Pediatrics, University of North Carolina at Chapel Hill, NC 27599, USA.

Despite its clinical significance, the mechanisms of joint morphogenesis are elusive. By combining laser-capture microdissection for RNA sampling with microarrays, we show that the setting in which joint-forming interzone cells develop is distinct from adjacent growth plate chondrocytes and is characterized by downregulation of chemokines, such as monocyte-chemoattractant protein-5 (MCP-5). Using in vivo, ex vivo, and in vitro approaches, we show that low levels of interzone-MCP-5 are essential for joint formation and contribute to proper growth plate organization. Mice lacking the TGF-β-type-II-receptor (TβRII) in their limbs (Tgfbr2(Prx1KO)), which lack joint development and fail chondrocyte hypertrophy, show upregulation of interzone-MCP-5. In vivo and ex vivo blockade of the sole MCP-5 receptor, CCR2, led to the rescue of joint formation and growth plate maturation in Tgfbr2(Prx1KO) but an acceleration of growth plate mineralization in control mice. Our study characterized the TβRII/MCP-5 axis as an essential crossroad for joint development and endochondral growth.
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http://dx.doi.org/10.1016/j.devcel.2012.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401383PMC
July 2012

Comparison of microCT and an inverse finite element approach for biomechanical analysis: results in a mesenchymal stem cell therapeutic system for fracture healing.

J Biomech 2012 Aug 4;45(12):2164-70. Epub 2012 Jul 4.

Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA.

An important concern in the study of fracture healing is the ability to assess mechanical integrity in response to candidate therapeutics in small-animal systems. In recent reports, it has been proposed that microCT image-derived densitometric parameters could be used as a surrogate for mechanical property assessment. Recently, we have proposed an inverse methodology that iteratively reconstructs the modulus of elasticity of the lumped soft callus/hard callus region by integrating both intrinsic mechanical property (from biomechanical testing) and geometrical information (from microCT) within an inverse finite element analysis (FEA) to define a callus quality measure. In this paper, data from a therapeutic system involving mesenchymal stem cells is analyzed within the context of comparing traditional microCT densitometric and mechanical property metrics. In addition, a novel multi-parameter regression microCT parameter is analyzed as well as our inverse FEA metric. The results demonstrate that the inverse FEA approach was the only metric to successfully detect both longitudinal and therapeutic responses. While the most promising microCT-based metrics were adequate at early healing states, they failed to track late-stage mechanical integrity. In addition, our analysis added insight to the role of MSCs by demonstrating accelerated healing and was the only metric to demonstrate therapeutic benefits at late-stage healing. In conclusion, the work presented here indicates that microCT densitometric parameters are an incomplete surrogate for mechanical integrity. Additionally, our inverse FEA approach is shown to be very sensitive and may provide a first-step towards normalizing the often challenging process of assessing mechanical integrity of healing fractures.
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http://dx.doi.org/10.1016/j.jbiomech.2012.05.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782612PMC
August 2012

Adipogenic differentiation of adipose tissue-derived human mesenchymal stem cells: effect of gastric bypass surgery.

Surg Endosc 2012 Dec 31;26(12):3449-56. Epub 2012 May 31.

Department of Surgery, Duke University Medical Center, 407 Crutchfield St, Durham, NC 27704, USA.

Background: Adipose tissue dysfunction is an important feature of obesity characterized by enlarged adipocytes and marked changes in secretion of cytokines. These changes result in insulin resistance, chronic vascular inflammation, oxidative stress, and activation of the renin-angiotensin system (RAS), eventually leading to type 2 diabetes, obesity-related hypertension, and cardiovascular disease (CVD). Several trials have shown that bariatric surgery significantly reduces these comorbidities. However, there is a gap in knowledge regarding the mechanisms whereby bariatric surgery reduces the burden of CVD in obese individuals.

Method: Mesenchymal stem cells (MSCs) were isolated from adipose tissue collected from three groups: (1) nonobese control subjects, (2) obese subjects undergoing gastric bypass surgery (GBS), and (3) subjects 1 year or more after GBS. In the study, MSCs were induced to adipogenic differentiation, and RAS-related gene expressions were determined by quantitative polymerase chain reaction. The effect of angiotensin II (Ang II) on adipogenic differentiation of MSCs also was investigated.

Results: Angiotensinogen mRNA levels in MSCs and differentiated adipocytes were significantly higher in the obese group than in the nonobese control subjects. Renin mRNA levels were significantly higher in the obese group MSCs than in the nonobese and post-GBS groups. Angiotensin-converting enzyme mRNA levels were significantly lower in the MSCs derived from the post-GBS group than in the obese and nonobese control subjects. Serum Ang II levels were significantly lower in the post-GBS group (52.1 ± 4.2 pg/ml) than in the nonobese (85.4 ± 12.4 pg/ml) and obese (84.7 ± 10.0 pg/ml) groups. Ang II treatment inhibited adipogenesis of MSCs in a dose-dependent manner. The inhibitory effect of Ang II was mainly abolished by PD123319, a receptor 2 blocker.

Conclusions: The adipogenesis of MSCs is inhibited by Ang II treatment. Obese individuals are characterized by an upregulation of the RAS-related gene expressions in adipose tissue. This upregulation resolves in post-GBS subjects.
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http://dx.doi.org/10.1007/s00464-012-2353-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587137PMC
December 2012

Systemically delivered insulin-like growth factor-I enhances mesenchymal stem cell-dependent fracture healing.

Growth Factors 2012 Aug 4;30(4):230-41. Epub 2012 May 4.

Department of Pediatrics, Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7039, USA.

In this study, we examined the effectiveness of systemic subcutaneous delivery of recombinant Insulin-like growth factor (IGF)-I concurrently with primary cultured bone marrow-derived mesenchymal stem cell (MSC) transplant on fracture repair. We found that the fracture callus volume increased in mice with a stabilized tibia fracture that received IGF-I+MSC when compared with that in either untreated or MSC alone treated mice. In evaluating the callus tissue components, we found that the soft and new bone tissue volumes were significantly increased in IGF-I+MSC recipients. Histological and in-situ hybridization analyses confirmed a characteristic increase of newly forming bone in IGF-I+MSC recipients and that healing progressed mostly through endochondral ossification. The increase in soft and new bone tissue volumes correlated with increased force and toughness as determined by biomechanical testing. In conclusion, MSC transplant concurrent with systemic delivery of IGF-I improves fracture repair suggesting that IGF-I+MSC could be a novel therapeutic approach in patients who have inadequate fracture repair.
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http://dx.doi.org/10.3109/08977194.2012.683188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752908PMC
August 2012

[Neuromodulation in the treatment of hand's scars].

Ann Ital Chir 2012 Mar-Apr;83(2):103-7

Department of Dermatology and Plastic, Reconstructive and Aesthetic Surgery, University of Rome La Sapienza Policlinico Umberto I, Rome, Italy.

Aim: In the present study, we investigated effects of a local anesthetic, in the treatment of pathologic scars.

Materials And Methods: this retrospective report describes our experience with 97 patients who underwent lidocaine 2% injections in surgical scars of the hand. The results were evaluated using 4 parameters: cutaneous structure, pain, thikness and colour of the scar.

Results: The mean outcome was the pain control. 2 out of 97 showed a 100% improvement in all the parameters. In 95 of 97 patients the improvement was between 60-100%.

Discussion: Lidocaine controls different pathways of inflammation. Flogosis is the first phase of cicatrization and so lidocaine could be used in the treatment of pathologic scars. A previous study confirms the role of lidocaine, injected to control the pillar pain in the carpal tunnel's surgery in the improvement of scars.

Conclusion: Lidocaine, as neuromodulation treatment, acts on inflammation, temperature, perfusion and partial pressure of oxygen.
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May 2012

Serum leptin levels are inversely correlated with omental gene expression of adiponectin and markedly decreased after gastric bypass surgery.

Surg Endosc 2012 May 17;26(5):1476-80. Epub 2011 Dec 17.

Department of Surgery, Duke University, 407 Crutchfield Street, Durham, NC 27704, USA.

Background: Adipose tissue is the most abundant endocrine tissue in the body, producing leptin, a hormone important in regulating hunger, and adiponectin, a hormone involved in insulin sensitivity and inflammation. This study aimed to assess the impact of gastric bypass surgery (GBS) on leptin levels and its relation to the adipose tissue expression of adiponectin.

Methods: Omental and subcutaneous adipose tissue and serum were obtained from 40 obese patients undergoing GBS, from 13 patients 1 year or more after GBS, and from 16 non-obese individuals with a body mass index of 20 to 29 kg/m(2). Adiponectin gene expression was measured by quantitative real-time polymerase chain reaction, and the gene expression was normalized for the GAPDH gene. Serum leptin and adiponectin were measured by a high-sensitivity enzymatic assay.

Results: Leptin levels were significantly lower in the post-GBS patients (19.8 ± 6.7) than in the pre-GBS patients (59.0 ± 5.1; P = 0.0001), and similar to those in the non-obese control subjects (18.2 ± 4; P = 0.8). Univariate analysis showed an inverse correlation between serum leptin levels and omental adiponectin gene expression (r = -0.32; P = 0.01).

Conclusions: Gastric bypass surgery results in resolution of the leptin resistance status that characterizes obese subjects. The study also demonstrated a significant correlation between leptin and adiponectin. This correlation provides preliminary evidence for studying a potential adiponectin-leptin cross-talking that may represent one of the physiologic pathways responsible for the regulation of food intake in humans.
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http://dx.doi.org/10.1007/s00464-011-2059-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391743PMC
May 2012

Omental gene expression of adiponectin correlates with degree of insulin sensitivity before and after gastric bypass surgery.

Obes Surg 2012 Mar;22(3):472-7

Department of Surgery, Duke University, 407 Crutchfield Street, Durham, NC 27704, USA.

Background: Circulating adiponectin is known to correlate negatively with insulin resistance in patients with obesity and diabetes. The aim of this study was to assess the effect of gastric bypass (GB) surgery on adiponectin gene expression in subcutaneous and omental adipose tissues.

Methods: Adipose tissues and plasma were obtained from 25 subjects undergoing GB surgery, 15 non-obese subjects, and 12 subjects after GB surgery. Real-time quantitative reverse transcription polymerase chain reaction was used for analysis of the adipose tissues. Adiponectin expression was normalized for glyceraldehyde 3-phosphate dehydrogenase and expressed as percentage of subject-matched subcutaneous expression which was given an arbitrary value of 100%. Insulin resistance was assessed by the homeostatic model assessment (HOMA). Circulating adiponectin was assayed by ELISA.

Results: Omental adiponectin gene expression was fivefold higher in subjects after GB when compared with age-matched morbidly obese subjects before GB (P < 0.01). There were no statistical differences in omental adiponectin gene expression observed in subjects after GB and age-matched non-obese subjects. For the entire cohort of subjects, there was a significant negative correlation between omental adiponectin expression and insulin resistance expressed by HOMA values (r = -0.62, P < 0.001). Circulating adiponectin was significantly lower (P < 0.05) in the obese group than in the non-obese and post-GB groups.

Conclusions: Omental adiponectin gene expression significantly increases after GB surgery reaching levels equal to age-matched non-obese subjects. Omental adiponectin expression has a significant negative correlation with the insulin resistance status.
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http://dx.doi.org/10.1007/s11695-011-0568-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381935PMC
March 2012

Necdin-E2F4 interaction provides insulin-sensitizing effect after weight loss induced by gastric bypass surgery.

Surg Obes Relat Dis 2013 Jan-Feb;9(1):94-9. Epub 2011 Nov 7.

Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27704, USA.

Background: The insulin-like growth factor-1 (IGF-1) signaling pathway promotes adipocyte differentiation and, therefore, insulin sensitivity by suppression of necdin expression, which represses peroxisome proliferator-activated receptor-gamma promoter activity by interaction with E2F4 in mouse adipocytes. The aim of the present study was to test the hypothesis that this pathway represents one of the mechanisms by which Roux-en-Y gastric bypass surgery (RYGB) induces resolution of insulin resistance.

Methods: Clinical samples were collected and the key biomarkers measured to test the hypothesis that the IGF-1 pathway represents 1 of the mechanisms by which RYGB induces resolution of insulin resistance in obese individuals.

Results: Free IGF-1 levels were significantly greater in the post-RYGB patients than in the pre-RYGB obese patients (2.55 ± 1.54 versus 1.32 ± .65 μg/L, P = .03) and similar to that in normal weight controls (2.54 ± 1.27 μg/L). Necdin and E2F4 gene expression in the adipose tissue was significantly downregulated after RYGB compared with obese and were similar to the levels observed in the controls. In mature human adipocytes cultured in vitro, treatment with des-IGF-1 induced downregulation of necdin and E2F4 gene expression in a dose-dependent manner (P = .01).

Conclusion: After RYGB, the insulin/IGF-1 signaling pathway is activated and could account for the observed decrease in the expression of necdin, which represses peroxisome proliferator-activated receptor-gamma promoter activity by interaction with E2F4. This could represent one of the mechanisms that induce resolution of insulin resistance after RYGB.
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http://dx.doi.org/10.1016/j.soard.2011.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302937PMC
July 2013

Metabolic control and bone health in adolescents with type 1 diabetes.

Int J Pediatr Endocrinol 2011 Oct 26;2011(1):13. Epub 2011 Oct 26.

Department of Pediatrics, Division of Endocrinology and Diabetes, Vanderbilt Children's Hospital, Nashville, TN, USA.

Background: Adults with type 1 diabetes (T1D) have decreased bone mineral density (BMD) and increased fracture risk, yet the etiologies remain elusive. Early detection of derangements in bone biomarkers during adolescence could lead to timely recognition. In adolescents with T1D, we evaluated the relationships between metabolic control, BMD, and bone anabolic and turnover markers.

Methods: Cross-sectional study of 57 adolescent subjects with T1D who had HbA1c consistently ≥ 9% (Poor Control, PC n = 27) or < 9% (Favorable Control, FC n = 30) for two years prior to enrollment. Subjects had T1DM for at least three years and were without diabetes complications, known celiac disease, or other chronic diseases.

Results: There were no differences between HbA1c groups in BMD, components of the IGF system, or 25-hydroxyvitamin D status. The prevalence of 25-hydroxyvitamin D abnormalities was similar to that seen in the general adolescent population. Few patients met the recommended dietary allowance (RDA) for vitamin D or calcium.

Conclusions: These data provide no evidence of association between degree of metabolic control and BMD in adolescents with T1D. Adolescents with T1D have a high prevalence of serum 25-hydroxyvitamin D abnormalities. Longitudinal studies are needed to evaluate the predictive value of vitamin D abnormalities on fracture risk.
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http://dx.doi.org/10.1186/1687-9856-2011-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215174PMC
October 2011

Minimally invasive reconstructive surgery for complex oncologic foot defects in children.

Plast Reconstr Surg 2011 Aug;128(2):603-605

Department of Plastic Surgery; La Sapienza University of Rome; Rome, Italy.

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http://dx.doi.org/10.1097/PRS.0b013e31821eefecDOI Listing
August 2011

Mesenchymal stem cells expressing insulin-like growth factor-I (MSCIGF) promote fracture healing and restore new bone formation in Irs1 knockout mice: analyses of MSCIGF autocrine and paracrine regenerative effects.

Stem Cells 2011 Oct;29(10):1537-48

Department of Pediatrics, Division of Pediatric Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Failures of fracture repair (nonunions) occur in 10% of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe, and feasible. The contributions of MSC to the reparative process can occur through autocrine and paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow-derived MSCs expressing insulin-like growth factor-I (MSC(IGF)), to promote these seed-and-soil actions of MSC to fully implement their regenerative abilities in fracture repair and nonunions. MSC(IGF) or traceable MSC(IGF)-Lac-Z were transplanted into wild-type or insulin-receptor-substrate knockout (Irs1(-/-)) mice with a stabilized tibia fracture. Healing was assessed using biomechanical testing, microcomputed tomography (μCT), and histological analyses. We found that systemically transplanted MSC(IGF) through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF-I adapted the response of transplanted MSC(IGF) to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF-I-induced osteoglastogenesis in MSCs was dependent of an intact IRS1-PI3K signaling. Furthermore, using Irs1(-/-) mice as a nonunion fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF-I on MSC restored the fracture new bone formation and promoted the occurrence of a well-organized callus that bridged the gap. A callus that was basically absent in Irs1(-/-) left untransplanted or transplanted with MSCs. We provided evidence of effects and mechanisms for transplanted MSC(IGF) in fracture repair and potentially to treat nonunions.
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http://dx.doi.org/10.1002/stem.697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622704PMC
October 2011

Approach to lipid screening as a risk marker for cardiovascular disease in pediatric patients with diabetes.

Front Endocrinol (Lausanne) 2011 11;2:47. Epub 2011 Oct 11.

Division of Pediatric Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill Chapel Hill, NC, USA.

Cardiovascular disease (CVD) is a well-known complication of diabetes mellitus (DM), and patients with DM are at an increased risk for early onset of CVD. Hyperglycemia is believed to be the primary mediator in premature development of atherosclerosis in patients with DM, but there are also derangements in cholesterol levels and inflammatory markers beyond the explanation of hyperglycemia. Although clinicians often screen for dyslipidemia as part of routine care for children and adolescents with DM, many do not feel comfortable treating this condition. Multiple guidelines exist to help clinicians with the prevention, screening, and treatment of CVD risk factors in pediatric patients with DM, but the guidelines do not always agree on screening intervals or medical treatment. Furthermore, the cost-effectiveness of medication use in this population has not been established. Research has advanced our understanding of the role of other biomarkers and radiologic studies of CVD risk, but these studies do not currently have a place in routine clinical practice. It is evident that the increased CVD risk in pediatric patients with DM is complex in origin and the optimal approach to managing dyslipidemia remains unclear. Therefore, an algorithm designed at the University of North Carolina (UNC), Division of Pediatric Endocrinology, is presented to help guide clinicians through screening and treatment of dyslipidemia in youth with DM.
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http://dx.doi.org/10.3389/fendo.2011.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355998PMC
August 2012

Mesenchymal stem cells at the intersection of cell and gene therapy.

Expert Opin Biol Ther 2010 Dec;10(12):1663-79

University of North Carolina at Chapel Hill, Department of Pediatrics, Chapel Hill, NC 27599-7239, USA.

Importance Of The Field: Mesenchymal stem cells have the ability to differentiate into osteoblasts, chondrocytes and adipocytes. Along with differentiation, MSCs can modulate inflammation, home to damaged tissues and secrete bioactive molecules. These properties can be enhanced through genetic-modification that would combine the best of both cell and gene therapy fields to treat monogenic and multigenic diseases.

Areas Covered In This Review: Findings demonstrating the immunomodulation, homing and paracrine activities of MSCs followed by a summary of the current research utilizing MSCs as a vector for gene therapy, focusing on skeletal disorders, but also cardiovascular disease, ischemic damage and cancer.

What The Reader Will Gain: MSCs are a possible therapy for many diseases, especially those related to the musculoskeletal system, as a standalone treatment, or in combination with factors that enhance the abilities of these cells to migrate, survive or promote healing through anti-inflammatory and immunomodulatory effects, differentiation, angiogenesis or delivery of cytolytic or anabolic agents.

Take Home Message: Genetically-modified MSCs are a promising area of research that would be improved by focusing on the biology of MSCs that could lead to identification of the natural and engrafting MSC-niche and a consensus on how to isolate and expand MSCs for therapeutic purposes.
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http://dx.doi.org/10.1517/14712598.2010.531257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057936PMC
December 2010

Use of glycol chitosan modified by 5beta-cholanic acid nanoparticles for the sustained release of proteins during murine embryonic limb skeletogenesis.

J Control Release 2010 May 28;144(1):101-8. Epub 2010 Jan 28.

Department of Pediatrics, Division of Pediatric Endocrinology, University of North Carolina at Chapel Hill, Mason Farm Road, Campus Box: 7039, Chapel Hill, NC 27599-7039, USA.

Murine embryonic limb cultures have invaluable roles in studying skeletogenesis. Substance delivery is an underdeveloped area in developmental biology that has primarily relied on Affi-Gel-Blue-agarose-beads. However, the lack of information about the efficiency of agarose-bead loading and release and difficulties for a single-bead implantation represent significant limitations. We optimized the use of glycol chitosan-5beta-cholanic acid conjugates (HGC) as a novel protein delivery system in mouse embryonic limbs. To this purpose, we loaded HGC either with recombinant Noggin, or bovine serum albumin (BSA). The size, morphology and stability of the protein-loaded-HGC were determined by transmission electron microscopy and dynamic-light-scattering. HGC-BSA and HGC-Noggin loading efficiencies were 80-90%. Time-course study revealed that Noggin and BSA were 80-90% released after 48 h. We developed several techniques to implant protein-loaded-HGC into murine embryonic joints from embryonic age E13.5 to E15.5, including a micro-injection system dispensing nanoliters. HGC did not interfere with skeletogenesis. Using CBR-3BA staining, we detected HGC nanoparticles within implanted tissues. Furthermore, a sustained release of BSA and Noggin was demonstrated in HGC-BSA and HGC-Noggin injected regions. HGC-released Noggin was biologically active in blocking the BMP signaling in in vitro mesenchyme limb micromasses as well as in ex-vivo limb cultures. Results reveal that HGC is a valuable protein-delivery system in developmental biology.
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http://dx.doi.org/10.1016/j.jconrel.2010.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3363971PMC
May 2010
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