Diabetes increases risk of lumbar spinal fusion complications: association with altered structure of newly formed bone at the fusion site.

Diabetes predisposes to spine degenerative diseases often requiring surgical intervention. However, the statistics on the prevalence of spinal fusion success and clinical indications leading to the revision surgery in diabetes are conflicting. The purpose of the presented retrospective observational study was to determine the link between diabetes and lumbar spinal fusion complications using a database of patients (n = 552, 45% male, age 54 ± 13.7 years) residing in the same community and receiving care at the same health care facility. Outcome measures included clinical indications and calculated risk ratio (RR) for revision surgery in diabetes. Paravertebral tissue recovered from a non-union site of diabetic and nondiabetic patients was analyzed for microstructure of newly formed bone. Diabetes increased the RR for revision surgery due to non-union complications (2.80; 95% CI, 1.12-7.02) and degenerative processes in adjacent spine segments (2.26; 95% CI, 1.45-3.53). In diabetes, a risk of revision surgery exceeded the RR for primary spinal fusion surgery by 44% (2.36 [95% CI, 1.58-3.52] vs 1.64 [95% CI, 1.16-2.31]), which was already 2-fold higher than diabetes prevalence in the studied community. Micro-CT of bony fragments found in the paravertebral tissue harvested during revision surgery revealed structural differences suggesting that newly formed bone in diabetic patients may be of compromised quality, as compared with that in nondiabetic patients. In conclusion, diabetes significantly increases the risk of unsuccessful lumbar spine fusion outcome requiring revision surgery. Diabetes predisposes to the degeneration of adjacent spine segments and pseudoarthrosis at the fusion sites, and affects the structure of newly formed bone needed to stabilize fusion.

Regulatory Effect of Osteocytes on Extramedullary and Bone Marrow Adipose Tissue Development and Function.

PURPOSE OF REVIEW: This review summarizes evidence on osteocyte support of extramedullary and bone marrow adipocyte development and discusses the role of endogenous osteocyte activities of nuclear receptors peroxisome proliferator-activated receptor gamma (PPARG) and alpha (PPARA) in this support. RECENT FINDINGS: PPARG and PPARA proteins, key regulators of glucose and fatty acid metabolism, are highly expressed in osteocytes. They play significant roles in the regulation of osteocyte secretome and osteocyte bioenergetics; both activities contributing to the levels of systemic energy metabolism in part through an effect on metabolic function of extramedullary and bone marrow adipocytes. The PPARs-controlled osteocyte endocrine/paracrine activities, including sclerostin expression, directly regulate adipocyte function, while the PPARs-controlled osteocyte fuel utilization and oxidative phosphorylation contribute to the skeletal demands for glucose and fatty acids, whose availability is under the control of adipocytes. Bone is an inherent element of systemic energy metabolism with PPAR nuclear receptors regulating osteocyte-adipocyte metabolic axes.

PPARG in osteocytes controls cell bioenergetics and systemic energy metabolism independently of sclerostin levels in circulation.

Objective: The skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels. Methods: In vivo and in vitro models of osteocyte-specific PPARG deletion, i.e. Dmp 1 Cre Pparγ flfl male and female mice (γOT KO ) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited Pparγ . As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress. Results: Circulating sclerostin levels of γOT KO male and female mice were not different from control mice. Male γOT KO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with "beiging" of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOT KO males suggested profound changes in cellular metabolism, fuel transport and usage, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, shifts in fuel utilization, and accumulation of reactive oxygen species (ROS). Conclusions: PPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditure via osteocyte metabolism. Highlights: Osteocytes function as a body energostat via their bioenergeticsPPARG protein acts as a "molecular break" of osteocyte mitochondrial activityPPARG deficiency activates TCA cycle, oxidative stress and ROS accumulationPPARG controls osteocyte insulin signaling and fuel utilization.

Osteocytes contribute via nuclear receptor PPAR-alpha to maintenance of bone and systemic energy metabolism.

Introduction: The view that bone and energy metabolism are integrated by common regulatory mechanisms is broadly accepted and supported by multiple strands of evidence. This includes the well-characterized role of the PPARγ nuclear receptor, which is a common denominator in energy metabolism and bone metabolism. Little is known, however, about the role of PPARα nuclear receptor, a major regulator of lipid metabolism in other organs, in bone. Methods: A side-by-side comparative study of 5-15 mo old mice with global PPARα deficiency (αKO) and mice with osteocyte-specific PPARα deficiency (αOTKO) in order to parse out the various activities of PPARα in the skeleton that are of local and systemic significance. This study included transcriptome analysis of PPARα-deficient osteocytes, and analyses of bone mass and bone microarchitecture, systemic energy metabolism with indirect calorimetry, and differentiation potential of hematopoietic and mesenchymal bone cell progenitors. These analyses were paired with in vitro studies of either intact or silenced for PPARα MLO-A5 cells to determine PPARα role in osteocyte bioenergetics. Results: In osteocytes, PPARα controls large number of transcripts coding for signaling and secreted proteins which may regulate bone microenvironment and peripheral fat metabolism. In addition, PPARα in osteocytes controls their bioenergetics and mitochondrial response to stress, which constitutes up to 40% of total PPARα contribution to the global energy metabolism. Similarly to αKO mice, the metabolic phenotype of αOTKO mice (both males and females) is age-dependent. In younger mice, osteocyte metabolism contributes positively to global energetics, however, with aging the high-energy phenotype reverts to a low-energy phenotype and obesity develops, suggesting a longitudinal negative effect of impaired lipid metabolism and mitochondrial dysfunction in osteocytes deficient in PPARα. However, bone phenotype was not affected in αOTKO mice except in the form of an increased volume of marrow adipose tissue in males. In contrast, global PPARα deficiency in αKO mice led to enlarged bone diameter with a proportional increase in number of trabeculae and enlarged marrow cavities; it also altered differentiation of hematopoietic and mesenchymal marrow cells toward osteoclast, osteoblast and adipocyte lineages, respectively. Discussion: PPARα role in bone is multileveled and complex. In osteocytes, PPARα controls the bioenergetics of these cells, which significantly contributes to systemic energy metabolism and their endocrine/paracrine function in controlling marrow adiposity and peripheral fat metabolism.

Diabetes and Impaired Fracture Healing: A Narrative Review of Recent Literature.

PURPOSE OF THE REVIEW: Diabetes mellitus is a chronic metabolic disorder commonly encountered in orthopedic patients. Both type 1 and type 2 diabetes mellitus increase fracture risk and impair fracture healing. This review examines complex etiology of impaired fracture healing in diabetes. RECENT FINDINGS: Recent findings point to several mechanisms leading to orthopedic complications in diabetes. Hyperglycemia and chronic inflammation lead to increased formation of advanced glycation end products and generation of reactive oxygen species, which in turn contribute to the disruption in osteoblast and osteoclast balance leading to decreased bone formation and heightening the risk of nonunion or delayed union as well as impaired fracture healing. The mechanisms attributing to this imbalance is secondary to an increase in pro-inflammatory mediators leading to premature resorption of callus cartilage and impaired bone formation due to compromised osteoblast differentiation and their apoptosis. Other mechanisms include disruption in the bone's microenvironment supporting different stages of healing process including hematoma and callus formation, and their resolution during bone remodeling phase. Complications of diabetes including peripheral neuropathy and peripheral vascular disease also contribute to the impairment of fracture healing. Certain diabetic drugs may have adverse effects on fracture healing. The pathophysiology of impaired fracture healing in diabetic patients is complex. This review provides an update of the most recent findings on how key mediators of bone healing are affected in diabetes.

Reconstitution of the host holobiont in germ-free born male rats acutely increases bone growth and affects marrow cellular content.

Integration of microbiota in a host begins at birth and progresses during adolescence, forming a multidirectional system of physiological interactions. Here, we present an instantaneous effect of natural, bacterial gut colonization on the acceleration of longitudinal and radial bone growth in germ-free born, 7-wk-old male rats. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in the tibia diaphysis. In addition, the number of small in size adipocytes increased, whereas the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats indicating that not only bone mass but also bone marrow environment is under control of gut microbiota signaling. The changes in bone status paralleled with a positive shift in microbiota composition toward short-chain fatty acids (SCFA)-producing microbes and a considerable increase in cecal SCFA concentrations, specifically butyrate. Furthermore, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels. Elevated serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase. Overall, the presented model of conventionalized germ-free rats could be used to study microbiota-based therapeutics for combatting dysbiosis-related bone disorders.

Report From the 6th International Meeting on Bone Marrow Adiposity (BMA2020).

The 6th International Meeting on Bone Marrow Adiposity (BMA) entitled "Marrow Adiposity: Bone, Aging, and Beyond" (BMA2020) was held virtually on September 9th and 10th, 2020. The mission of this meeting was to facilitate communication and collaboration among scientists from around the world who are interested in different aspects of bone marrow adiposity in health and disease. The BMA2020 meeting brought together 198 attendees from diverse research and clinical backgrounds spanning fields including bone biology, endocrinology, stem cell biology, metabolism, oncology, aging, and hematopoiesis. The congress featured an invited keynote address by Ormond MacDougald and ten invited speakers, in addition to 20 short talks, 35 posters, and several training and networking sessions. This report summarizes and highlights the scientific content of the meeting and the progress of the working groups of the BMA society (http://bma-society.org/).

PPARG in osteocytes controls sclerostin expression, bone mass, marrow adiposity and mediates TZD-induced bone loss.

The peroxisome proliferator activated receptor gamma (PPARG) nuclear receptor regulates energy metabolism and insulin sensitivity. In this study, we present novel evidence for an essential role of PPARG in the regulation of osteocyte function, and support for the emerging concept of the conjunction between regulation of energy metabolism and bone mass. We report that PPARG is essential for sclerostin production, a recently approved target to treat osteoporosis. Our mouse model of osteocyte-specific PPARG deletion (Dmp1CrePparγflfl or γOTKO) is characterized with increased bone mass and reduced bone marrow adiposity, which is consistent with upregulation of WNT signaling and increased bone forming activity of endosteal osteoblasts. An analysis of osteocytes derived from γOTKO and control mice showed an excellent correlation between PPARG and SOST/sclerostin at the transcript and protein levels. The 8 kb sequence upstream of Sost gene transcription start site possesses multiple PPARG binding elements (PPREs) with at least two of them binding PPARG with dynamics reflecting its activation with full agonist rosiglitazone and correlating with increased levels of Sost transcript and sclerostin protein expression (Pearson's r = 0.991, p = 0.001). Older γOTKO female mice are largely protected from TZD-induced bone loss providing proof of concept that PPARG in osteocytes can be pharmacologically targeted. These findings demonstrate that transcriptional activities of PPARG are essential for sclerostin expression in osteocytes and support consideration of targeting PPARG activities with selective modulators to treat osteoporosis.

Nonenzymatic and Trophic Activities of Carboxypeptidase E Regulate Bone Mass and Bioenergetics of Skeletal Stem Cells in Mice.

Bone and energy metabolism are integrated by common regulatory mechanisms. Carboxypeptidase E (CPE), also known as obesity susceptibility protein or neurotrophic factor-α1, is recognized for its function in processing prohormones, including proinsulin and pro-opiomelanocortin polypeptide. Independent of its enzymatic activity, CPE may also act as a secreted factor with divergent roles in neuroprotection and cancer growth; however, its role in the regulation of bone mass and skeletal cell differentiation is unknown. Male mice with global deficiency in CPE are characterized with profound visceral obesity, low bone mass in both appendicular and axial skeleton, and high volume of marrow fat. Interestingly, although metabolic deficit of CPE KO mice develops early in life, bone deficit develops in older age, suggesting that CPE bone-specific activities differ from its enzymatic activities. Indeed, mutated CPE knockin (mCPE KI) mice ectopically expressing CPE-E342Q, a mutated protein lacking enzymatic activity, develop the same obese phenotype and accumulate the same volume of marrow fat as CPE KO mice, but their bone mass is normal. In addition, differentiation of marrow hematopoietic cells toward tartrate-resistant acid phosphatase-positive multinucleated osteoclasts is highly increased in CPE KO mice, but normal in mCPE KI mice. Moreover, in murine skeletal stem cells, nonenzymatic trophic CPE has activated ERK signaling, increased cell proliferation and increased mitochondrial activity. Treatment of preosteoblastic cells with intact or mutated recombinant CPE led to a transient accumulation of small lipid droplets, increased oxidative phosphorylation, and increased cellular dependence on fatty acids as fuel for energy production. In human marrow aspirates, CPE expression increases up to 30-fold in osteogenic conditions. These findings suggest that nonenzymatic and trophic activities of CPE regulate bone mass, whereas marrow adiposity is controlled by CPE enzymatic activity. Thus, CPE can be positioned as a factor regulating simultaneously bone and energy metabolism through a combination of shared and distinct mechanisms. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Marrow Fat-a New Target to Treat Bone Diseases?

PURPOSE OF REVIEW: The goal of this review is to summarize recent findings on marrow adipose tissue (MAT) function and to discuss the possibility of targeting MAT for therapeutic purposes. RECENT FINDINGS: MAT is characterized with high heterogeneity which may suggest both that marrow adipocytes originate from multiple different progenitors and/or their phenotype is determined by skeletal location and environmental cues. Close relationship to osteoblasts and heterogeneity suggests that MAT consists of cells representing spectrum of phenotypes ranging from lipid-filled adipocytes to pre-osteoblasts. We propose a term of adiposteoblast for describing phenotypic spectrum of MAT. Manipulating with MAT activity in diseases where impairment in energy metabolism correlates with bone functional deficit, such as aging and diabetes, may be beneficial for both. Paracrine activities of MAT might be considered for treatment of bone diseases. MAT has unrecognized potential, either beneficial or detrimental, to regulate bone homeostasis in physiological and pathological conditions. More research is required to harness this potential for therapeutic purposes.

Injectable nanosilica-chitosan microparticles for bone regeneration applications.

This study was aimed at assessing the effects of silica nanopowder incorporation into chitosan-tripolyphosphate microparticles with the ultimate goal of improving their osteogenic properties. The microparticles were prepared by simple coacervation technique and silica nanopowder was added at 0% (C), 2.5% (S1), 5% (S2) and 10% (S3) (w/w) to chitosan. We observed that this simple incorporation of silica nanopowder improved the growth and proliferation of osteoblasts along the surface of the microparticles. In addition, the composite microparticles also showed the increased expression of alkaline phosphatase and osteoblast specific genes. We observed a significant increase ( p < 0.05) in the expression of alkaline phosphatase by the cells growing on all sample groups compared to the control (C) groups at day 14. The morphological characterization of these microparticles through scanning electron microscopy showed that these microparticles were well suited to be used as the injectable scaffolds with perfectly spherical shape and size. The incorporation of silica nanopowder altered the nano-roughness of the microparticles as observed through atomic force microscopy scans with roughness values going down from C to S3. The results in this study, taken together, show the potential of chitosan-tripolyphosphate-silica nanopowder microparticles for improved bone regeneration applications.

Reciprocal regulation of PPARγ and RUNX2 activities in marrow mesenchymal stem cells: Fine balance between p38 MAPK and Protein Phosphatase 5.

PURPOSE OF REVIEW: Post-translational modifications (PTMs), specifically serine phosphorylation, are essential for determination and tuning up an activity of many proteins, including those that are involved in the control of gene transcription. Transcription factors PPARγ2 and RUNX2 are essential for mesenchymal stem cell (MSC) commitment to either adipocyte or osteoblast lineage. This review is summarizing current knowledge how serine phosphorylation PTMs regulate activities of both transcription factors and MSCs lineage commitment. RECENT FINDING: Both PPARγ2 and RUNX2 transcriptional activities are regulated by similar PTMs, however with an opposite outcome. The same p38 MAPK mediates serine phosphorylation that leads to activation of RUNX2 and inactivation of PPARγ2. The process of protein phosphorylation is balanced with a process of protein dephosphorylation. Protein phosphatase 5 simultaneously dephosphorylates both proteins, which results in activation of PPARγ2 and inactivation of RUNX2. SUMMARY: This review provides a summary of the "yinyang" fine-tuned mechanism by which p38 MAPK and PP5 regulate MSCs lineage commitment.

Marrow Adipose Tissue: Skeletal Location, Sexual Dimorphism, and Response to Sex Steroid Deficiency.

Marrow adipose tissue (MAT) is unique with respect to origin, metabolism, and function. MAT is characterized with high heterogeneity which correlates with skeletal location and bone metabolism. This fat depot is also highly sensitive to various hormonal, environmental, and pharmacologic cues to which it responds with changes in volume and/or metabolic phenotype. We have demonstrated previously that MAT has characteristics of both white (WAT) and brown (BAT)-like or beige adipose tissue, and that beige phenotype is attenuated with aging and in diabetes. Here, we extended our analysis by comparing MAT phenotype in different locations within a tibia bone of mature C57BL/6 mice and with respect to the presence of sex steroids in males and females. We report that MAT juxtaposed to trabecular bone of proximal tibia (pMAT) is characterized by elevated expression of beige fat markers including Ucp1, HoxC9, Prdm16, Tbx1, and Dio2, when compared with MAT located in distal tibia (dMAT). There is also a difference in tissue organization with adipocytes in proximal tibia being dispersed between trabeculae, while adipocytes in distal tibia being densely packed. Higher trabecular bone mass (BV/TV) in males correlates with lower pMAT volume and higher expression of beige markers in the same location, when compared with females. However, there is no sexual divergence in the volume and transcriptional profile of dMAT. A removal of ovaries in females resulted in decreased cortical bone mass and increased volume of both pMAT and dMAT, as well as volume of gonadal WAT (gWAT). Increase in pMAT volume was associated with marked increase in Fabp4 and Adiponectin expression and relative decrease in beige fat gene markers. A removal of testes in males resulted in cortical and trabecular bone loss and the tendency to increased volume of both pMAT and dMAT, despite a loss of gWAT. Orchiectomy did not affect the expression of white and beige adipocyte gene markers. In conclusion, expression profile of beige adipocyte gene markers correlates with skeletal location of active bone remodeling and higher BV/TV, however bone loss resulted from sex steroid deficiency is not proportional to MAT expansion at the same skeletal location.

Diabetes, bone and glucose-lowering agents: basic biology.

Skeletal fragility often accompanies diabetes and does not appear to correlate with low bone mass or trauma severity in individuals with diabetes. Instead (and in contrast to those with osteoporotic bone disease), bone remodelling and bone turnover are compromised in both type 1 and type 2 diabetes, contributing to defective bone material quality. This review is one of a pair discussing the relationship between diabetes, bone and glucose-lowering agents; an accompanying review is provided in this issue of Diabetologia by Ann Schwartz (DOI: 10.1007/s00125-017-4283-6 ). This review presents basic science evidence that, alongside other organs, bone is affected in diabetes via impairments in glucose metabolism, toxic effects of glucose oxidative derivatives (advance glycation end-products [AGEs]), and via impairments in bone microvascular function and muscle endocrine function. The cellular and molecular basis for the effects of diabetes on bone are discussed, as is the impact of diabetes on the stem cell niche and fracture healing. Furthermore, the safety of clinically approved glucose-lowering therapies and the possibility of developing a single therapy that would be beneficial for both insulin sensitisation and diabetes bone syndrome are outlined.

Protein Phosphatase PP5 Controls Bone Mass and the Negative Effects of Rosiglitazone on Bone through Reciprocal Regulation of PPARγ (Peroxisome Proliferator-activated Receptor γ) and RUNX2 (Runt-related Transcription Factor 2).

Peroxisome proliferator-activated receptor γ (PPARγ) and runt-related transcription factor 2 (RUNX2) are key regulators of mesenchymal stem cell (MSC) differentiation toward adipocytes and osteoblasts, respectively. Post-translational modifications of these factors determine their activities. Dephosphorylation of PPARγ at Ser-112 is required for its adipocytic activity, whereas phosphorylation of RUNX2 at serine 319 (Ser-319) promotes its osteoblastic activity. Here we show that protein phosphatase 5 (PP5) reciprocally regulates each receptor by targeting each serine. Mice deficient in PP5 phosphatase have increased osteoblast numbers and high bone formation, which results in high bone mass in the appendicular and axial skeleton. This is associated with a substantial decrease in lipid-containing marrow adipocytes. Indeed, in the absence of PP5 the MSC lineage allocation is skewed toward osteoblasts and away from lipid accumulating adipocytes, although an increase in beige adipocyte gene expression is observed. In the presence of rosiglitazone, PP5 translocates to the nucleus, binds to PPARγ and RUNX2, and dephosphorylates both factors, resulting in activation of PPARγ adipocytic and suppression of RUNX2 osteoblastic activities. Moreover, shRNA knockdown of PP5 results in cells refractory to rosiglitazone treatment. Lastly, mice deficient in PP5 are resistant to the negative effects of rosiglitazone on bone, which in wild type animals causes a 50% decrease in trabecular bone mass. In conclusion, PP5 is a unique phosphatase reciprocally regulating PPARγ and RUNX2 activities in marrow MSC.

FKBP51 Null Mice Are Resistant to Diet-Induced Obesity and the PPARγ Agonist Rosiglitazone.

FK506-binding protein-51 (FKBP51) is a molecular cochaperone recently shown to be a positive regulator of peroxisome proliferator-activated receptor (PPAR)γ, the master regulator of adipocyte differentiation and function. In cellular models of adipogenesis, loss of FKBP51 not only reduced PPARγ activity but also reduced lipid accumulation, suggesting that FKBP51 knock-out (KO) mice might have insufficient development of adipose tissue and lipid storage ability. This model was tested by examining wild-type (WT) and FKBP51-KO mice under regular and high-fat diet conditions. Under both diets, FKBP51-KO mice were resistant to weight gain, hepatic steatosis, and had greatly reduced white adipose tissue (WAT) but higher amounts of brown adipose tissue. Under high-fat diet, KO mice were highly resistant to adiposity and exhibited reduced plasma lipids and elevated glucose and insulin tolerance. Profiling of perigonadal and sc WAT revealed elevated expression of brown adipose tissue lineage genes in KO mice that correlated increased energy expenditure and a shift of substrate oxidation to carbohydrates, as measured by indirect calorimetry. To directly test PPARγ involvement, WT and KO mice were fed rosiglitazone agonist. In WT mice, rosiglitazone induced whole-body weight gain, increased WAT mass, a shift of substrate oxidation to lipids, and elevated expression of PPARγ-regulated lipogenic genes in WAT. In contrast, KO mice had reduced rosiglitazone responses for these parameters. Our results identify FKBP51 as an important regulator of PPARγ in WAT and as a potential new target in the treatment of obesity and diabetes.

Skeletal Metabolism, Fracture Risk, and Fracture Outcomes in Type 1 and Type 2 Diabetes.

Fracture risk is significantly increased in both type 1 and type 2 diabetes, and individuals with diabetes experience worse fracture outcomes than normoglycemic individuals. Factors that increase fracture risk include lower bone mass in type 1 diabetes and compromised skeletal quality and strength despite preserved bone density in type 2 diabetes, as well as the effects of comorbidities such as diabetic macro- and microvascular complications. In this Perspective, we assess the developing scientific knowledge regarding the epidemiology and pathophysiology of skeletal fragility in patients with diabetes and the emerging data on the prediction, treatment, and outcomes of fractures in individuals with type 1 and type 2 diabetes.