Though prevalent in white postmenopausal women, osteoporosis occurs in all populations and at all ages and has significant physical, psychosocial, and financial consequences. Risks for osteoporosis (reflected by low bone mineral density [BMD]) and for fracture overlap but are not identical. More attention should be paid to skeletal health in persons with conditions associated with secondary osteoporosis. Clinical risk factors have an important but poorly validated role in determining who should have BMD measurement, in assessing fracture risk, and in determining who should be treated. Adequate calcium and vitamin D intake is crucial to develop optimal peak bone mass and to preserve bone mass throughout life. Supplementation with these 2 nutrients may be necessary in persons not achieving recommended dietary intake. Gonadal steroids are important determinants of peak and lifetime bone mass in men, women, and children. Regular exercise, especially resistance and high-impact activities, contributes to development of high peak bone mass and may reduce risk of falls in older persons. Assessment of bone mass, identification of fracture risk, and determination of who should be treated are the optimal goals when evaluating patients for osteoporosis. Fracture prevention is the primary treatment goal for patients with osteoporosis. Several treatments have been shown to reduce the risk of osteoporotic fractures, including those that enhance bone mass and reduce the risk or consequences of falls. Adults with vertebral, rib, hip, or distal forearm fractures should be evaluated for osteoporosis and given appropriate therapy.

ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.

On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression, and genetic determinants. Early MAT formation in mice is conserved, while later development is strain dependent. Proximal, but not distal, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2, Cebpa and Cebpb. Humans also have increased distal marrow fat unsaturation. We define proximal ‘regulated’ MAT (rMAT) as single adipocytes interspersed with active hematopoiesis, whereas distal ‘constitutive’ MAT (cMAT) has low hematopoiesis, contains larger adipocytes, develops earlier, and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, hematopoiesis and whole-body metabolism.

Maternally expressed gene 3 (MEG3) is an imprinted gene belonging to the imprinted DLK1–MEG3 locus located at chromosome 14q32.3 in humans. Its mouse ortholog, Meg3, also known as gene trap locus 2 (Gtl2), is located at distal chromosome 12. The MEG3 gene encodes a long noncoding RNA (lncRNA) and is expressed in many normal tissues. MEG3 gene expression is lost in an expanding list of primary human tumors and tumor cell lines. Multiple mechanisms contribute to the loss of MEG3 expression in tumors, including gene deletion, promoter hypermethylation, and hypermethylation of the intergenic differentially methylated region. Re-expression of MEG3 inhibits tumor cell proliferation in culture and colony formation in soft agar. This growth inhibition is partly the result of apoptosis induced by MEG3. MEG3 induces accumulation of p53 (TP53) protein, stimulates transcription from a p53-dependent promoter, and selectively regulates p53 target gene expression. Maternal deletion of the Meg3 gene in mice results in skeletal muscle defects and perinatal death. Inactivation of Meg3 leads to a significant increase in expression of angiogenesis-promoting genes and microvessel formation in the brain. These lines of evidence strongly suggest that MEG3 functions as a novel lncRNA tumor suppressor.

MEG3 is a maternally expressed imprinted gene suggested to function as a non-coding RNA. Our previous studies suggest that MEG3 has a function of tumor suppression. The tumor suppressor p53 plays a central role in tumor suppression and mediates the functions of many other tumor suppressors. Therefore, we hypothesized that MEG3 functions through activation of p53. We found that transfection of expression constructs for MEG3 and its isoforms results in a significant increase in p53 protein levels and dramatically stimulates p53-dependent transcription from a p53-responsive promoter. Using this as the functional assay, we demonstrated that the open reading frames encoded by MEG3 transcripts are not required for MEG3 function, and the folding of MEG3 RNA is critical to its function, supporting the concept that MEG3 functions as a non-coding RNA. We further found that MEG3 stimulates expression of the growth differentiation factor 15 (GDF15) by enhancing p53 binding to the GDF15 gene promoter. Interestingly, MEG3 does not stimulate p21 CIP1 expression, suggesting that MEG3 can regulate the specificity of p53 transcriptional activation. p53 degradation is mainly mediated by the mouse double minute 2 homolog (MDM2). We found that MDM2 levels were down-regulated in cells transfected with MEG3, suggesting that MDM2 suppression contributes at least in part to p53 accumulation induced by MEG3. Finally, we found that MEG3 is able to inhibit cell proliferation in the absence of p53. These data suggest that MEG3 non-coding RNA may function as a tumor suppressor, whose action is mediated by both p53-dependent and p53-independent pathways.

SUMMARY The adipocyte-derived hormone adiponectin promotes metabolic and cardiovascular health. Circulating adiponectin increases in lean states such as caloric restriction (CR), but the reasons for this paradox remain unclear. Unlike white adipose tissue (WAT), bone marrow adipose tissue (MAT) increases during CR, and both MAT and serum adiponectin increase in many other clinical conditions. Thus, we investigated if MAT contributes to circulating adiponectin. We find that adiponectin secretion is greater from MAT than from WAT. Notably, specific inhibition of MAT formation in mice results in decreased circulating adiponectin during CR, despite unaltered adiponectin expression in WAT. Inhibiting MAT formation also alters skeletal muscle adaptation to CR, suggesting that MAT exerts systemic effects. Finally, we reveal that both MAT and serum adiponectin increase during cancer therapy in humans. These observations identify MAT as an endocrine organ that contributes significantly to increased serum adiponectin during CR, and perhaps in other adverse states.