In human tissues, normal homeostasis requires intricately balanced interactions between cells and the network of secreted proteins known as the extracellular matrix. These cooperative interactions involve numerous cytokines acting through specific cell-surface receptors. When the balance between the cells and the extracellular matrix is perturbed, disease can result. This is clearly evident in the interactions mediated by the cytokine transforming growth factor β (TGF-β). TGF-β is a member of a family of dimeric polypeptide growth factors that includes bone morphogenic proteins and activins. All of these growth factors share a cluster of conserved cysteine residues that form a common cysteine . . .

Role of transforming growth factor beta in human disease.

Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(02)08706-8.pdf

Pathogenesis of bone fragility in women and men.

The pathologies of many infectious, autoimmune and malignant diseases are influenced by the profiles of cytokine production in pro-inflammatory (TH1) and anti-inflammatory (TH2) T cells. Interindividual differences in cytokine profiles appear to be due, at least in part, to allelic polymorphism within regulatory regions of cytokine gene. Many studies have examined the relationship between cytokine gene polymorphism, cytokine gene expression in vitro, and the susceptibility to and clinical severity of diseases. A review of the findings of these studies is presented. An on-line version featuring appropriate updates is accessible from the World Wide Web site, http://www.pam.bris.ac.uk/services/GAI/cytokine4.htm.

/pdf/cytokine-gene-polymorphism-in-human-disease-on-line-mb7yqxfth5.pdf

Cytokine gene polymorphism in human disease: on-line databases.

There is now a large body of evidence suggesting that the decline in ovarian function with menopause is associated with spontaneous increases in proinflammatory cytokines. The cytokines that have obtained the most attention are IL-1, IL-6, and TNF-alpha. The exact mechanisms by which estrogen interferes with cytokine activity are still incompletely known but may potentially include interactions of the ER with other transcription factors, modulation of nitric oxide activity, antioxidative effects, plasma membrane actions, and changes in immune cell function. Experimental and clinical studies strongly support a link between the increased state of proinflammatory cytokine activity and postmenopausal bone loss. Preliminary evidence suggests that these changes also might be relevant to vascular homeostasis and the development of atherosclerosis. Better knowledge of the mechanisms and the time course of these interactions may open new avenues for the prevention and treatment of some of the most prevalent and important disorders in postmenopausal women.

Changes in proinflammatory cytokine activity after menopause.

Transforming growth factor-β (TGF-β) is both abundant in bone and an important regulator of bone metabolism. A TC transition at nucleotide 29 in the signal sequence region of the TGF-β1 gene results in a LeuPro substitution at amino acid position 10. The possible association of this polymorphism with bone mass and the prevalence of osteoporosis has now been investigated in a total of 287 postmenopausal women from two regions (Obu City, Aichi Prefecture, and Sanda City, Hyogo Prefecture) of Japan. A significant association of TGF-β1 genotype with bone mass was detected in both populations; bone mineral density (BMD) at the lumbar spine was greater in individuals with the CC genotype than in those with the TT or TC genotype. The frequency of vertebral fractures was significantly lower in individuals with the CC genotype than in those with the TC or TT genotypes. For each region, multivariable logistic regression analysis revealed that the frequency of the T allele was significantly higher in subjects with osteoporosis than in controls. Also, the serum concentration of TGF-β1 in individuals with the CC genotype was significantly higher than that in age-matched subjects with the TC or TT genotype in osteoporotic or osteopenic as well as healthy control groups. These results suggest that the T/C polymorphism of the TGF-β1 gene is one of the genetic determinants of bone mass and that the T allele is an independent risk factor for the genetic susceptibility to osteoporosis in postmenopausal Japanese women. Thus, analysis of the TGF-β1 genotype may be useful in the prevention and management of osteoporosis.

Association of a Polymorphism of the Transforming Growth Factor‐β1 Gene with Genetic Susceptibility to Osteoporosis in Postmenopausal Japanese Women

Interventions for Treating Sarcopenia: A Systematic Review and Meta-Analysis of Randomized Controlled Studies.

Aim: Sarcopenia-related falls and fractures are becoming an emerging problem as a result of rapid aging worldwide. We aimed to investigate the prevalence of sarcopenia by estimating the muscle mass of the arms and legs of patients with and without hip fracture.

Methods:  This cross-sectional study examined 357 patients immediately after a hip fracture (the HF group) and in 2511 patients from an outpatient clinic who did not have a hip fracture (the NF group) at single institution in Japan. We carried out whole-body dual energy X-ray absorptiometry to analyze body composition with skeletal muscle mass index (SMI; lean mass / height2) and bone mineral density (BMD). We carried out stepwise logistic regression analysis to determine the factors associated with a hip fracture.

Results:  Lower appendicular SMI (P   0.95). In multivariate analysis, the presence of sarcopenia, older age and lower BMD were associated with the occurrence of a hip fracture (OR 1.476, P = 0.002; OR 1.103, P < 0.001; OR 0.082, P < 0.001; respectively).

Conclusion:  This study showed a higher prevalence of sarcopenia and more reduced leg muscle mass in patients after a hip fracture than in the outclinic patients who did not have hip fractures. The results imply sarcopenia can be a risk factor for a hip fracture. Geriatr Gerontol Int 2013; 13: 413–420.

High prevalence of sarcopenia and reduced leg muscle mass in Japanese patients immediately after a hip fracture.

A method to protect the hips during falls could effectively reduce the incidence of hip fractures. We report the results of the first hip protector trial in Japan, performed between July 1996, and September 1999. One hundred and sixty-four elderly female residents of nursing homes, with Activities of Daily Living above the wheelchair level, agreed to participate in this study. Among them, 88 were randomly selected to wear a hip protector and 76 controls did not. All falls and resulting injuries were recorded daily. In anthropometric measurements and ultrasonic bone evaluation, no significant differences were found between the two groups, except in height. During an average of 377 days, the wearers and the non-wearers fell a total of 131 and 90 times, respectively. Among the wearers, there were two non-hip fractures and one hip fracture, so the annual hip fracture rate was calculated at 1.2%, against 8 hip fractures among the non-wearers, or 9.7% per year. The hip fracture rate was significantly lower among the wearers than non-wearers, while the annual number of falls per subject and the distribution of fallers remained the same. According to Cox’s proportional hazard regression analysis, the effect of the hip protector on hip fracture prevention was independent of anthropometric data, ultrasonic bone assessment values or number of falls. Moreover, even after limiting the subjects to fallers only, the annual hip fracture rate in non-wearers was higher than in wearers (19.8% vs 2.0%) and the annual hip fracture rate per fall in wearers was lower than that in non-wearers (0.8% vs 8.2%). It was thus concluded that the hip protector is a beneficial device for the prevention of hip fractures.

https://link.springer.com/content/pdf/10.1007/s001980170132.pdf

Hip Fracture Prevention Trial Using Hip Protectors in Japanese Nursing Homes

Sarcopenia-related falls and fractures among women with osteoporosis are becoming an emerging problem because of rapid aging worldwide. We aimed to investigate the association between sarcopenia, given by the muscle mass of the arms and legs, and osteoporotic vertebral fracture (OVF) among female patients. This cross-sectional study examined 216 women with fresh OVF (OVF group) diagnosed by magnetic resonance imaging and 1,608 women from an outpatient clinic who did not have a OVF [non-fracture (NF) group]. We performed whole-body dual-energy X-ray absorptiometry to analyze body composition, including skeletal muscle mass index (SMI; lean mass/height2) and bone mineral density (BMD). We used stepwise logistic regression analysis to determine the risk factors associated with OVF. After controlling for age, the OVF group showed lower appendicular SMI (5.62 vs. 5.97 kg/m2, P < 0.001), lower arm SMI (1.36 vs. 1.42 kg/m2, P = 0.004), lower leg SMI (4.27 vs. 4.55 kg/m2, P < 0.001), and higher prevalence of sarcopenia (42.3 vs. 25.9 %, P < 0.001), compared with the NF group. Reduced leg muscle mass and presence of sarcopenia were independent risk factors for acute OVF in multivariate analysis (odds ratio = 1.4, P = 0.002; odds ratio = 1.96, P < 0.001, respectively). We found higher prevalence of sarcopenia and lower leg muscle mass among patients with acute OVF compared with patients who did not have an OVF. These results suggest that sarcopenia may be a risk factor for OVF.

Atsushi Harada

Papers

Association of a Polymorphism of the Transforming Growth Factor‐β1 Gene with Genetic Susceptibility to Osteoporosis in Postmenopausal Japanese Women

Interventions for Treating Sarcopenia: A Systematic Review and Meta-Analysis of Randomized Controlled Studies.

High prevalence of sarcopenia and reduced leg muscle mass in Japanese patients immediately after a hip fracture.

Hip Fracture Prevention Trial Using Hip Protectors in Japanese Nursing Homes

Sarcopenia and sarcopenic leg as potential risk factors for acute osteoporotic vertebral fracture among older women.