From the gut to the strut: where inflammation reigns, bone abstains

Abstract

C o m m e n t a r y2 0 4A new player in sex steroid deficiency-related bone lossOsteoporosis is a leading cause of morbidity in the increasing population of aging adults. In postmenopausal women, fracture incidence far exceeds the combined incidence of breast cancer, stroke, and myocardial infarction. Bone loss arises from accelerated resorption by osteoclasts, which outpaces the accompanying increase in bone formation by osteoblasts (1). Postmenopausal osteoporosis has traditionally been solely attributed to declining estrogen levels. However, the rapid loss of bone during the late perimenopausal transition, particularly when estrogen levels are relatively normal, is proposed to be mediated, at least in part, by rising follicle-stimulating hormone levels (FSH levels) (2, 3). Nonetheless, these hormonal changes do not fully explain the increased bone formation, high BM T cell counts, or macrophage activation that have been noted across the menopausal transition (4). Alterations in immune cell function have largely been attributed to increased production of TNFα, which further enhances osteoclast formation and function (5, 6). Consistent with this, ablation of the Tnfa gene in mice prevents gonadectomy-induced bone loss, osteoclast and osteoblast activation, and accompanying immune cell abberations (5). However, the mechanisms that drive TNFα production during hypogonadal states remain relatively unclear. In this issue, Li et al. (7) show that gut microbiota play a fundamental role in the enhanced TNFα production that occurs upon the induction of estrogen deficiency in mice. It has previously been shown that lowering the inflammatory burden does suppress the effects of estrogen deficiency. For example, TNFα or IL-1 blockade in early postmenopausal women decreases bone resorption markers (8). Likewise, mice in which Tnfa or Il6 is deleted are relatively resistant to ovariectomy-induced bone loss (9). Li et al. evaluated how gut microbiota contribute to the inflammation seen with estrogen deficiency by using a strategy in which mice raised in an environment devoid of gut bacterial colonization (germ-free mice) were chemically castrated with leuprolide (7). Impressively, these hypogonadal, germ-free mice did not experience the marked bone loss that occurred in hypogonadal mice with unperturbed gut flora. Likewise, osteoclast numbers were not increased in germ-free mice. Even more impressive was the observation that the reintroduction of flora into germ-free mice reversed the osteoprotection exerted by an absence of microbiota; this, in essence, proved a fundamental role for gut microbiota in regulating skeletal integrity. Mice raised in a germ-free environment are indeed known to have increased bone mass and fewer osteoclasts (10). The findings of Li et al. now suggest that the same pathways are responsible for the bone loss accompanying sex steroid deficiency. Germ-free mice maintain barrier functionWhat is the mechanism through which gut microbiota mediate bone loss during sex steroid deficiency? It is widely acce...

Structural and functional changes of gut microbiota in ovariectomized rats and their correlations with altered bone mass

“…The immune system plays a critical role in mediating GM-related effects on the regulation of bone mass. Cytokines and chemokines such as TNF-α, CCL-2, IL-10, SERT (Serotonin Transporter) and Tph1 may be possible mediators between the GM and steroid deficiency-induced osteoporosis [ 41 , 42 ]. Therefore, further mechanistic studies, including fecal microbiota transplantation, are needed to verify the causality of gut microbiota on steroid deficiency-induced osteoporosis.…”

Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice

“…We also showed that LPS administration prior to injury elevates Tlr5/7/8 transcription in the joint [ 10 , 21 ]. TNF-α promotes osteoclastogenesis by increasing RANK-L expression in bone marrow cells and therefore elevating the number of osteoclast precursor cells [ 20 , 22 , 23 , 24 ].…”

Insulin‐Stimulated Bone Blood Flow and Bone Biomechanical Properties Are Compromised in Obese, Type 2 Diabetic OLETF Rats

“…Moreover, other pathogenic processes associated with endothelial dysfunction might negatively impact bone in T2D. For example, increased inflammation, cellular adhesion, and oxidative stress might also contribute to the changes in bone structural and material properties that occur in T2D. Impaired bone endothelial function is just one potential mechanism by which T2D results in bone fragility.…”