Background. Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered.

https://downloads.hindawi.com/journals/ije/2014/235060.pdf

Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis.

Although it has long been recognized that inflammation, a consequence of immune-driven processes, significantly impacts bone turnover, the degree of centralization of skeletal and immune functions has begun to be dissected only recently. It is now recognized that formation of osteoclasts, the bone resorbing cells of the body, is centered on the key osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL). Although numerous inflammatory cytokines are now recognized to promote osteoclast formation and skeletal degradation, with just a few exceptions, RANKL is now considered to be the final downstream effector cytokine that drives osteoclastogenesis and regulates osteoclastic bone resorption. The biological activity of RANKL is moderated by its physiological decoy receptor, osteoprotegerin (OPG). New discoveries concerning the sources and regulation of RANKL and OPG in physiological bone turnover as well as under pathological (osteoporotic) conditions continue to be made, opening a window to the complex regulatory processes that control skeletal integrity and the depth of integration of the skeleton within the immune response. This paper will examine the interconnection between bone turnover and the immune system and the implications thereof for physiological and pathological bone turnover.

/pdf/the-role-of-inflammatory-cytokines-the-rankl-opg-axis-and-4noyak3jzd.pdf

The Role of Inflammatory Cytokines, the RANKL/OPG Axis, and the Immunoskeletal Interface in Physiological Bone Turnover and Osteoporosis

Objective: Age-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration. Methods: A limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010. Results and discussion: We present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population.

/pdf/osteoblasts-in-osteoporosis-past-emerging-and-future-1ffddk5u47.pdf

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Skeletal disorders are among the leading debilitating factors affecting millions of people worldwide. The use of stem cells for tissue repair has raised many promises in various medical fields, including skeletal disorders. Mesenchymal stem cells (MSCs) are multipotent stromal cells with mesodermal and neural crest origin. These cells are one of the most attractive candidates in regenerative medicine, and their use could be helpful in repairing and regeneration of skeletal disorders through several mechanisms including homing, angiogenesis, differentiation, and response to inflammatory condition. The most widely studied sources of MSCs are bone marrow (BM), adipose tissue, muscle, umbilical cord (UC), umbilical cord blood (UCB), placenta (PL), Wharton’s jelly (WJ), and amniotic fluid. These cells are capable of differentiating into osteoblasts, chondrocytes, adipocytes, and myocytes in vitro. MSCs obtained from various sources have diverse capabilities of secreting many different cytokines, growth factors, and chemokines. It is believed that the salutary effects of MSCs from different sources are not alike in terms of repairing or reformation of injured skeletal tissues. Accordingly, differential identification of MSCs’ secretome enables us to make optimal choices in skeletal disorders considering various sources. This review discusses and compares the therapeutic abilities of MSCs from different sources for bone and cartilage diseases.

/pdf/mesenchymal-stem-cells-amazing-remedies-for-bone-and-hywctmot4v.pdf

Mesenchymal stem cells: amazing remedies for bone and cartilage defects

Inflammation and insulin resistance are common in several chronic diseases, such as obesity, type 2 diabetes mellitus, metabolic syndrome, cancer, and cardiovascular diseases. Various studies show a relationship between these two factors, although the mechanisms involved are not completely understood yet. Here, we discuss the molecular basis of insulin resistance and inflammation and the molecular aspects on inflammatory pathways interfering in insulin action. Moreover, we explore interventions based on molecular targets for preventing or treating correlated disorders, advances for a better characterization, and understanding of the mechanisms and mediators involved in the different inflammatory and insulin resistance conditions. Finally, we address biotechnological studies for the development of new potential therapies and interventions.

https://downloads.hindawi.com/journals/bmri/2012/379024.pdf

Molecular Targets Related to Inflammation and Insulin Resistance and Potential Interventions

Background
Insulin resistance is associated with a proinflammatory state that promotes the development of complications such as type 2 diabetes mellitus (T2DM) and atherosclerosis. The metabolic stimuli that initiate and propagate proinflammatory cytokine production and the cellular origin of proinflammatory cytokines in insulin resistance have not been fully elucidated. Circulating proinflammatory monocytes show signs of enhanced inflammation in obese, insulin resistant subjects and are thus a potential source of proinflammatory cytokine production. The specific, circulating metabolic factors that might stimulate monocyte inflammation in insulin resistant subjects are poorly characterized. We have examined whether saturated nonesterified fatty acids (NEFA) and insulin, which increase in concentration with developing insulin resistance, can trigger the production of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in human monocytes.

/pdf/palmitate-and-insulin-synergistically-induce-il-6-expression-kwyfcral2p.pdf

Palmitate and insulin synergistically induce IL-6 expression in human monocytes.

Skeletal changes accompanying aging are associated with both increased risk of fractures and impaired fracture healing, which, in turn, is due to compromised bone regeneration potential. These changes are associated with increased serum levels of selected proinflammatory cytokines, e.g., tumor necrosis factor α (TNF-α). We have used a unique model of bone regeneration to demonstrate (1) that aged-related deficits in direct bone formation can be restored to young mice by treatment with TNF blockers and (2) that the cyclin-dependent kinase inhibitor p21 is a candidate for mediation of the osteoinhibitory effects of TNF. It has been hypothesized recently that TNF antagonists may represent novel anabolic agents, and we believe that the data presented here represent a successful test of this hypothesis. © 2010 American Society for Bone and Mineral Research

Restoration of regenerative osteoblastogenesis in aged mice: modulation of TNF.

5538 Background: A non-surgical alternative for treating CIN2/3 would be desirable for women of childbearing age due to a risk of cervical incompetency in subsequent pregnancies following surgical treatments. PepCan consists of four current good manufacturing-grade HPV 16 E6 peptides and a Candida skin testing reagent (Candin, Nielsen Biosciences), because of Candida’s ability to regress common warts in humans, and to promote T cell proliferation and interleukin-12 secretion in vitro. Methods: In this single-center, randomized, double-blind Phase II study (NCT02481414), women with biopsy-confirmed CIN2/3 were treated with PepCan or Candida (1:1). Four intradermal injections were given 3 weeks apart which were followed with two visits 6 months apart. Histological responses (primary endpoint) were assessed using quadrant biopsies, and those whose lesions regressed to no CIN were considered to be responders. Regression rate of each treatment group was compared to that of a historical placebo group following the same treatment schedule. A sample size of 35 per arm had 93% power to test the null hypothesis that π = 0.29 (historical control placebo rate) and detect a difference of 0.31 with a two-sided type I error of 5%. Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse Events Version 4. Results: Of 99 subjects screened, 81 (81.8%) qualified for vaccination, and 80 received at least one vaccination. No dose-limiting toxicity was observed. With the intention-to-treat analysis, PepCan showed 30.8% efficacy (12 of 39, p=0.16) while Candida demonstrated 47.6% efficacy (20 of 42, p=0.0004). Likewise, with the per-protocol analysis, PepCan showed 45.8% efficacy (11 of 24, p=0.06) and Candida showed 62.1% efficacy (18 of 29, p=0.0002). There was no difference between efficacy of PepCan and Candida. Conclusions: PepCan and Candida treatments are safe. Only Candida was effective in inducing histological regression in the intention-to-treat and per-protocol analyses. Candida could become a new treatment for CIN2/3 by eliciting general immune stimulation similar to checkpoint inhibitors. Clinical trial information: NCT02481414 . [Table: see text]

A peptide-based human papillomavirus therapeutic vaccine, PepCan, or Candida adjuvant alone in treatment of cervical intraepithelial neoplasia 2/3 (CIN2/3).

Abstract The apolipoprotein E gene (APOE) confers the greatest genetic risk factor for Alzheimer’s disease (AD), wherein the ε4 allele confers an elevated risk compared with the ε3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murine Apoe gene has undergone targeted replacement with sequences encoding human ApoE3 or ApoE4 (ApoE-TR mice). Such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without amyloid β-peptide (Aβ) accumulation. We crossed ApoE3-TR and ApoE4-TR mice with a transgenic line that accumulates human Aβ1-42. In male ApoE3-TR mice, introduction of Aβ caused aberrations in glucose tolerance and in membrane translocation of astrocytic glucose transporter 1 (GLUT1). Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of Aβ had no significant effects because of a trend toward perturbation of the baseline values.

https://www.eneuro.org/content/eneuro/10/4/ENEURO.0376-22.2023.full.pdf

Amyloid β-Peptide Effects on Glucose Regulation Are Dependent on Apolipoprotein E Genotype

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Papers

Palmitate and insulin synergistically induce IL-6 expression in human monocytes.

Restoration of regenerative osteoblastogenesis in aged mice: modulation of TNF.

A peptide-based human papillomavirus therapeutic vaccine, PepCan, or Candida adjuvant alone in treatment of cervical intraepithelial neoplasia 2/3 (CIN2/3).

Amyloid β-Peptide Effects on Glucose Regulation Are Dependent on Apolipoprotein E Genotype