Smad-dependent mechanisms of inflammatory bone destruction

Abstract

Homeostatic bone remodelling becomes disturbed in a variety of pathologic conditions that affect the skeleton, including inflammatory diseases. Rheumatoid arthritis is the prototype of an inflammatory arthritis characterised by chronic inflammation, progressive cartilage destruction and focal bone erosions and is a prime example for a disease with disturbed bone homeostasis. The inflammatory milieu favours the recruitment and activation of osteoclasts, which have been found to be the cells that are primarily responsible for bone erosions in many animal models of inflammatory arthritis. Among the inflammatory modulators, members of the transforming growth factor (TGF)-β super family are shown to be important regulators in osteoclastogenesis with Smad-mediated signalling being crucial for inducing osteoclast differentiation. These findings have opened a new field for exploring mechanisms of osteoclast differentiation under inflammatory conditions. Recent studies have shown that the TGF-β superfamily members TGF-β1, myostatin and activin A directly regulate osteoclast differentiation through mechanisms that depend on the RANKL–RANK interplay. These growth factors transduce their signals through type I and II receptor serine/threonine kinases, thereby activating the Smad pathway. In this review, we describe the impact of inflammation-induced Smad signalling in osteoclast development and subsequently bone erosion in rheumatoid arthritis.

CD109 deficiency induces osteopenia with an osteoporosis‐like phenotype in vivo

“…This difference in p-values between ES/BS and OV/BV might suggest that bone erosion exceeds osteoid formation in CD109 −/− mice. Together with previous studies showing that CD109 is a negative regulator of TGF-β signaling (Finnson et al, 2006;Hagiwara et al, 2010;Sunagawa et al, 2016;Zhang et al, 2015), our hypothesis is that CD109 deficiency induces aberrations in bone metabolism in vivo via TGF-β signaling (Asagiri & Takayanagi, 2007;Edwards et al, 2010;Fennen, Pap, & Dankbar, 2016;Gingery et al, 2008;Itonaga et al, 2004), whereas CD109 may regulate osteoclastogenesis by a mechanism independent of TGF-β signaling in vitro (Wang et al, 2013). Notably, this suggests that CD109 −/− mice might be useful as an alternative osteoporosis animal model that requires no procedures such as ovariectomy, orchiectomy, hindlimb immobilization or calcium-restricted diet (Miller, Bowman, & Jee, 1995).…”

MiR-596 inhibits osteoblastic differentiation and cell proliferation by targeting Smad3 in steroid-induced osteonecrosis of femoral head

“…SMAD protein family belongs to the intracellular signaling protein, which was first identified in invertebrates by gene screening [19]. Studies have shown that the SMAD protein family plays a key role in bone formation [20,21]. Smad3 is a member of the SMAD protein family, which has been proved to be a critical factor in the normal maintenance of the bone [22].…”

Gene Therapy for Follistatin Mitigates Systemic Metabolic Inflammation and Post-Traumatic Osteoarthritis in High-Fat Diet-Induced Obese Mice

“…For example, mice grown with FST overexpression via global knock-in exhibited an impaired bone structure (43). However, in adult diabetic mice, FST was shown to accelerate bone regeneration by inhibiting myostatin-induced osteoclastogenesis (44,45). Furthermore, it has been reported that FST down-regulates BMP2-driven osteoclast activation (46).…”