Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder

Abstract

The high cardiovascular mortality associated with chronic kidney disease (CKD) is caused in part by the CKD-mineral bone disorder (CKD-MBD) syndrome. The CKD-MBD consists of skeletal, vascular and cardiac pathology caused by metabolic derangements produced by kidney disease. The prevalence of osteopenia/osteoporosis resulting from the skeletal component of the CKD-MBD, renal osteodystrophy (ROD), in patients with CKD exceeds that of the general population and is a major public health concern. That CKD is associated with compromised bone health is widely accepted, yet the mechanisms underlying impaired bone metabolism in CKD are not fully understood. Therefore, clarification of the molecular mechanisms by which CKD produces ROD is of crucial significance. We have shown that activin A, a member of the transforming growth factor (TGF)-β super family, is an important positive regulator of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis with Smad-mediated signaling being crucial for inducing osteoclast development and function. Recently, we have demonstrated systemic activation of activin receptors and activin A levels in CKD mouse models, such as diabetic CKD and Alport (AL) syndrome. In these CKD mouse models, bone remodeling caused by increased osteoclast numbers and activated osteoclastic bone resorption was observed and treatment with an activin receptor ligand trap repaired CKD-induced-osteoclastic bone resorption and stimulated individual osteoblastic bone formation, irrespective of parathyroid hormone (PTH) elevation. These findings have opened a new field for exploring mechanisms of activin A-enhanced osteoclast formation and function in CKD. Activin A appears to be a strong candidate for CKD-induced high-turnover ROD. Therefore, the treatment with the decoy receptor for activin A might be a good candidate for treatment for CKD-induced osteopenia or osteoporosis, indicating that the new findings from in these studies will lead to the identification of novel therapeutic targets for CKD-related and osteopenia and osteoporosis in general. In this review, we describe the impact of CKD-induced Smad signaling in osteoclasts, osteoblasts and vascular cells in CKD.

<p>Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD): Current Perspectives</p>

“…Reversal and attenuation of these features of CKD-MBD was observed with inhibition of ActRIIA signalling. [38][39][40]…”

Pathogenesis and management of vascular calcification in CKD and dialysis patients

“…It acts synergistically with RANK‐L (also produced by osteoblasts and bone marrow stromal cells) and promotes osteoclastogenesis and osteoclast function. It has been implicated in causing osteogenic differentiation of VSMCs . A novel therapeutic intervention has been the use of ligand traps for Activin‐A.…”

“…It has been implicated in causing osteogenic differentiation of VSMCs. 22 A novel therapeutic intervention has been the use of ligand traps for Activin-A. Ligand traps are recombinant molecules that contain the ligand-binding domain of the receptor combined with a portion of an immunoglobulin molecule and serve to bind and inhibit the effects of the ligand.…”

The Association between the Activin A Serum Level and Carotid Intima-Media Thickness in Chronic Kidney Disease Patients

“…Activin A levels are known to increase in CKD [ 7 , 28 ], and its mechanism in vascular calcification might act via ActRllA receptor signaling [ 7 ]. The binding of activin A with this receptor will produce an intracellular activin A signal that activates smad2 phosphorylation through the RANKL pathway that forms the smad2 complex [ 29 , 30 ].…”