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1.  Differences in Fat and Muscle Mass Associated With a Functional Human Polymorphism in a Post-Transcriptional BMP2 Gene Regulatory Element 
Journal of cellular biochemistry  2009;107(6):1073-1082.
A classic morphogen, bone morphogenetic protein 2 (BMP2) regulates the differentiation of pluripotent mesenchymal cells. High BMP2 levels promote osteogenesis or chondrogenesis and low levels promote adipogenesis. BMP2 inhibits myogenesis. Thus, BMP2 synthesis is tightly controlled. Several hundred nucleotides within the 3′ untranslated regions of BMP2 genes are conserved from mammals to fishes indicating that the region is under stringent selective pressure. Our analyses indicate that this region controls BMP2 synthesis by post-transcriptional mechanisms. A common A to C single nucleotide polymorphism (SNP) in the BMP2 gene (rs15705, +A1123C) disrupts a putative post-transcriptional regulatory motif within the human ultra-conserved sequence. In vitro studies indicate that RNAs bearing the A or C alleles have different protein binding characteristics in extracts from mesenchymal cells. Reporter genes with the C allele of the ultra-conserved sequence were differentially expressed in mesenchymal cells. Finally, we analyzed MRI data from the upper arm of 517 healthy individuals aged 18–41 years. Individuals with the C/C genotype were associated with lower baseline subcutaneous fat volumes (P = 0.0030) and an increased gain in skeletal muscle volume (P = 0.0060) following resistance training in a cohort of young males. The rs15705 SNP explained 2–4% of inter-individual variability in the measured parameters. The rs15705 variant is one of the first genetic markers that maybe exploited to facilitate early diagnosis, treatment, and/or prevention of diseases associated with poor fitness. Furthermore, understanding the mechanisms by which regulatory polymorphisms influence BMP2 synthesis will reveal novel pharmaceutical targets for these disabling conditions.
doi:10.1002/jcb.22209
PMCID: PMC4147943  PMID: 19492344
Bone Morphogenetic Protein 2 (BMP2); Messenger RNA (mRNA); Post-Transcriptional Gene Regulation; Mesenchymal Cells; Single Nucleotide Polymorphism (SNP); Fitness; Population Genetics
2.  Bisphosphonate Treatment for Children With Disabling Conditions 
Fractures are a frequent source of morbidity in children with disabling conditions. The assessment of bone density in this population is challenging, because densitometry is influenced by dynamic forces affecting the growing skeleton and may be further confounded by positioning difficulties and surgical hardware. First-line treatment for pediatric osteoporosis involves conservative measures, including optimizing the management of underlying conditions, maintaining appropriate calcium and vitamin D intake, encouraging weight-bearing physical activity, and monitoring measurements of bone mineral density. Bisphosphonates are a class of medications that increase bone mineral density by inhibiting bone resorption. Although bisphosphonates are commonly prescribed for treatment of adult osteoporosis, their use in pediatric patients is controversial because of the lack of long-term safety and efficacy data.
doi:10.1016/j.pmrj.2013.10.009
PMCID: PMC4037384  PMID: 24368091
3.  Genetic Influences on Vitamin D Status and Forearm Fracture Risk in African American Children 
Journal of Investigative Medicine  2012;60(6):902-906.
We sought to investigate the relationship between newly identified genetic variants and vitamin D levels and fracture risk in healthy African American (Black) children. This case-control study included children of both sexes, ages 5 to 9 years, with and without forearm fractures. Serum 25-hydroxy vitamin D levels, bone mineral density, body mass index and calcium/vitamin D intake were measured in 130 individuals (n = 60 cases and n = 70 controls). The five variants tested were located in the GC gene (rs2282679), in the NADSYN1 gene (rs12785878 and rs3829251), and in the promoter region of the CYP2R1 gene (rs2060793 and rs104741657). Associations between single nucleotide polymorphisms (SNPs) and vitamin D levels were tested using an ANCOVA. Associations between SNPs and fracture status were tested using logistic regression. The GC gene variant was associated with vitamin D levels (p = 0.038). None of the SNPs were associated with fracture status in young Blacks. These results suggest that the variants tested, which are associated with circulating vitamin D levels in Whites, are not associated with fracture status in healthy Black children. Additional research is required to discover the genetics of fracture risk in Blacks.
doi:10.231/JIM.0b013e3182567e2a
PMCID: PMC3404230  PMID: 22613962
fracture risk; single nucleotide polymorphism; vitamin D levels; body mass index; bone mineral density
4.  Addressing the gaps: sex differences in osteoarthritis of the knee 
An introduction to the accompanying three papers.
doi:10.1186/2042-6410-4-4
PMCID: PMC3571922  PMID: 23374401
Sex differences in response to sex steroids; Knee biomechanics and osteoarthritis; Pain perception in knee osteoarthritis; Musculoskeletal tissues; Estrogen; Testosterone; Rapid actions; Ligaments; Tendons; Bones; Animal models of osteoarthritis; Knee as an organ
5.  Hormonal modulation of connective tissue homeostasis and sex differences in risk for osteoarthritis of the knee 
Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies.
doi:10.1186/2042-6410-4-3
PMCID: PMC3583799  PMID: 23374322
Bone; Estrogen; Ligaments; Osteoarthritis; Sex differences; Sex steroids; Tendon; Testosterone
6.  Mosaic Overgrowth with Fibroadipose Hyperplasia is Caused by Somatic Activating Mutations in PIK3CA 
Nature genetics  2012;44(8):928-933.
The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2, or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells of a patient with an unclassified syndrome of congenital, progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated p.His1047Leu mutation in PIK3CA, which encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in 10 further patients with overlapping syndromes identified either p.His1047Leu or a second cancer-associated mutation, p.His1047Arg, in 9 cases. Affected dermal fibroblasts showed enhanced basal and EGF-stimulated phosphatidylinositol-3,4,5-trisphosphate (PIP3) generation and concomitant activation of downstream signaling. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.
doi:10.1038/ng.2332
PMCID: PMC3461408  PMID: 22729222
7.  Mechanical contributors to sex differences in idiopathic knee osteoarthritis 
The occurrence of knee osteoarthritis (OA) increases with age and is more common in women compared with men, especially after the age of 50 years. Recent work suggests that contact stress in the knee cartilage is a significant predictor of the risk for developing knee OA. Significant gaps in knowledge remain, however, as to how changes in musculoskeletal traits disturb the normal mechanical environment of the knee and contribute to sex differences in the initiation and progression of idiopathic knee OA. To illustrate this knowledge deficit, we summarize what is known about the influence of limb alignment, muscle function, and obesity on sex differences in knee OA. Observational data suggest that limb alignment can predict the development of radiographic signs of knee OA, potentially due to increased stresses and strains within the joint. However, these data do not indicate how limb alignment could contribute to sex differences in either the development or worsening of knee OA. Similarly, the strength of the knee extensor muscles is compromised in women who develop radiographic and symptomatic signs of knee OA, but the extent to which the decline in muscle function precedes the development of the disease is uncertain. Even less is known about how changes in muscle function might contribute to the worsening of knee OA. Conversely, obesity is a stronger predictor of developing knee OA symptoms in women than in men. The influence of obesity on developing knee OA symptoms is not associated with deviation in limb alignment, but BMI predicts the worsening of the symptoms only in individuals with neutral and valgus (knock-kneed) knees. It is more likely, however, that obesity modulates OA through a combination of systemic effects, particularly an increase in inflammatory cytokines, and mechanical factors within the joint. The absence of strong associations of these surrogate measures of the mechanical environment in the knee joint with sex differences in the development and progression of knee OA suggests that a more multifactorial and integrative approach in the study of this disease is needed. We identify gaps in knowledge related to mechanical influences on the sex differences in knee OA.
doi:10.1186/2042-6410-3-28
PMCID: PMC3560206  PMID: 23259740
Knee joint; Limb alignment; Muscle function; Obesity; Osteoarthritis; Sex differences
8.  Neural and psychosocial contributions to sex differences in knee osteoarthritic pain 
People with osteoarthritis (OA) can have significant pain that interferes with function and quality of life. Women with knee OA have greater pain and greater reductions in function and quality of life than men. In many cases, OA pain is directly related to sensitization and activation of nociceptors in the injured joint and correlates with the degree of joint effusion and synovial thickening. In some patients, however, the pain does not match the degree of injury and continues after removal of the nociceptors with a total joint replacement. Growth of new nociceptors, activation of nociceptors in the subchondral bone exposed after cartilage degradation, and nociceptors innervating synovium sensitized by inflammatory mediators could all augment the peripheral input to the central nervous system and result in pain. Enhanced central excitability and reduced central inhibition could lead to prolonged and enhanced pain that does not directly match the degree of injury. Psychosocial variables can influence pain and contribute to pain variability. This review explores the neural and psychosocial factors that contribute to knee OA pain with an emphasis on differences between the sexes and gaps in knowledge.
doi:10.1186/2042-6410-3-26
PMCID: PMC3583673  PMID: 23244577
Osteoarthritis; Pain; Sex differences; Gender; Nociceptor; Central sensitization; Psychosocial; Catastrophizing
9.  Assessment and management of the orthopedic and other complications of Proteus syndrome 
Purpose
A multidisciplinary workshop was convened at the National Institutes of Health (NIH) to discuss the management of the orthopedic and other complications of Proteus syndrome (PS), a progressive, disproportionate overgrowth disorder. While PS poses many complex challenges, the focus of the workshop was the management of the asymmetric and disorganized skeletal overgrowth that characterizes this multisystem disorder.
Methods
Workshop participants developed recommendations for clinical research and patient management and surveillance to maximize the benefits and reduce the risks of surgical and other interventions.
Results
Recommendations for clinical care and management included assessments of skeletal overgrowth and its progression with modalities such as X-ray, magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry, and computerized tomography (CT) imaging. The recommendations also cover the assessment of non-orthopedic complications of PS that significantly impact surgical risk, such as pulmonary embolism and lung bullae. Surgical considerations in PS include assessment of the contribution of contractures to deformities and prophylactic soft-tissue release, aggressive and early use of epiphysiodesis and epiphysiostasis, amputation, and spinal bracing.
Conclusion
Decisions on the timing of orthopedic procedures in children with PS are challenging because they entail balancing the risks of intervention in this high-risk and complex population against the increasing morbidity that patients experience with progressive bony overgrowth. If surgery is delayed too long, the condition may become inoperable. We hope that these recommendations will help clinicians gather appropriate data and assist their patients in making timely treatment decisions.
doi:10.1007/s11832-011-0350-6
PMCID: PMC3179535  PMID: 23024722
Proteus syndrome; Overgrowth; Scoliosis; Limb-length inequality
10.  Bone Quality: Educational Tools for Patients, Physicians, and Educators 
Background
Defining bone quality remains elusive. From a patient perspective bone quality can best be defined as an individual’s likelihood of sustaining a fracture. Fracture risk indicators and performance measures can help clinicians better understand individual fracture risk. Educational resources such as the Web can help clinicians and patients better understand fracture risk, communicate effectively, and make decisions concerning diagnosis and treatment.
Questions/purposes
We examined four questions: What tools can be used to identify individuals at high risk for fracture? What clinical performance measures are available? What strategies can help ensure that patients at risk for fracture are identified? What are some authoritative Web sites for educating providers and patients about bone quality?
Methods
Using Google, PUBMED, and trademark names, we reviewed the literature using the terms “bone quality” and “osteoporosis education.” Web site legitimacy was evaluated using specific criteria. Educational Web sites were limited to English-language sites sponsored by nonprofit organizations
Results
The Fracture Risk Assessment Tool® (FRAX®) and the Fracture Risk Calculator (FRC) are reliable means of assessing fracture risk. Performance measures relating to bone health were developed by the AMA convened Physician Consortium for Performance Improvement® and are included in the Physician Quality Reporting Initiative. In addition, quality measures have been developed by the Joint Commission. Strategies for identifying individuals at risk include designating responsibility for case finding and intervention, evaluating secondary causes of osteoporosis, educating patients and providers, performing cost-effectiveness evaluation, and using information technology. An abundance of authoritative educational Web sites exists for providers and patients.
Conclusions
Effective clinical indicators, performance measures, and educational tools to better understand and identify fracture risk are now available. The next challenge is to encourage broader use of these resources so that individuals at high risk for fracture will not just be identified but will also adhere to therapy.
doi:10.1007/s11999-011-1809-y
PMCID: PMC3126939  PMID: 21400004
11.  Breakout Session: Sex/Gender and Racial/Ethnic Disparities in the Care of Osteoporosis and Fragility Fractures 
Background
Recent epidemiologic and clinical data suggest men and racial and ethnic minorities may receive lower-quality care for osteoporosis and fragility fractures than female and nonminority patients. The causes of such differences and optimal strategies for their reduction are unknown.
Questions/purposes
A panel was convened at the May 2010 American Academy of Orthopaedic Surgeons/Orthopaedic Research Society/Association of Bone and Joint Surgeons Musculoskeletal Healthcare Disparities Research Symposium to (1) assess current understanding of sex/gender and racial/ethnic disparities in the care of osteoporosis and after fragility fractures, (2) define goals for improving the equity and quality of care, and (3) identify strategies for achieving these goals.
Where are we now?
Participants identified shortcomings in the quality of care for osteoporosis and fragility fractures among male and minority populations and affirmed a need for novel strategies to improve the quality and equity of care.
Where do we need to go?
Participants agreed opportunities exist for health professionals to contribute to improved osteoporosis management and secondary fracture prevention. They agreed on a need to define standards of care and management for osteoporosis and fragility fractures and develop strategies to involve physicians and other health professionals in improving care.
How do we get there?
The group proposed strategies to improve the quality and equity of osteoporosis and care after fragility fractures. These included increased patient and physician education, with identification of “champions” for osteoporosis care within and outside of the healthcare workforce; creation of incentives for hospitals and physicians to improve care; and research comparing the effectiveness of approaches to osteoporosis screening and fracture management.
doi:10.1007/s11999-011-1859-1
PMCID: PMC3111803  PMID: 21424834
12.  A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome 
The New England journal of medicine  2011;365(7):611-619.
BACKGROUND
The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state.
METHODS
We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots.
RESULTS
Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation.
CONCLUSIONS
The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K–AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.)
doi:10.1056/NEJMoa1104017
PMCID: PMC3170413  PMID: 21793738
13.  AKT1 polymorphisms are associated with risk for metabolic syndrome 
Human Genetics  2010;129(2):129-139.
Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that make up metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) (n = 175; age 40–65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. In older African-American and European American subjects (Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p < 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-010-0910-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-010-0910-8
PMCID: PMC3020305  PMID: 21061022
14.  Clinical Delineation and Natural History of the PIK3CA-Related Overgrowth Spectrum** 
Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype–phenotype correlation, this cannot yet be confirmed. © The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.
doi:10.1002/ajmg.a.36552
PMCID: PMC4320693  PMID: 24782230
somatic mosaicism; PIK3CA gene; fibroadipose overgrowth; segmental overgrowth; macrodactyly; CLOVES syndrome

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