The α-Isoform of p38 MAPK Specifically Regulates Arthritic Bone Loss

Abstract

Pharmacological inhibitors have provided evidence for the key role of p38 MAPK in osteoclast differentiation and in inflammation-induced bone loss. However, these inhibitors block more than one of the four p38 isoforms, usually p38α and p38β, and sometimes also other kinases such as JNK3. We show in this study that p38α is the main p38 isoenzyme expressed in the osteoclast precursors and in the mature osteoclasts. p38α as well as its downstream substrates were phosphorylated in osteoclast progenitors stimulated by TNF-α. Using Mx-cre-mediated conditional gene inactivation we demonstrated that mice lacking p38α were protected against TNF-α-induced bone destruction at the site of inflammation as well as against TNF-α-mediated systemic bone loss. The bone protection was associated to decreased osteoclast numbers in vivo as well as a decreased IL-1β expression in the inflamed tissue and in the isolated monocytes. The phenotype was cell autonomous because, similarly to p38α-deficient cells, knockdown of p38α in monocytes resulted in a decreased osteoclast differentiation in vitro. It was not caused by major changes in RANKL-mediated ERK or JNK activation but rather associated to an increased NF-κB activation caused by a decrease in IκBα recovery. Thus, our data show that developing specific inhibitors of the α-isoenzyme of p38 would be beneficial for the treatment of inflammation-induced bone destruction as observed in rheumatoid arthritis.

Increased bone density and resistance to ovariectomy‐induced bone loss in FoxP3‐transgenic mice based on impaired osteoclast differentiation

“…Histomorphometric analysis was performed on methacrylate-embedded undecalcified plastic sections stained with von Kossa's stain and with Goldner's stain for bone. Histologic and immunohistologic analyses were performed as described previously (30,31). All quantifications were performed by digital image analysis (OsteoMeasure; OsteoMetrics).…”

Focus on the p38 MAPK signaling pathway in bone development and maintenance

“…Osteoclast precursors and mature osteoclasts highly express p38a but no other p38 members. 45 Once again, first evidence highlighting the role of p38a in osteoclastogenesis has come from in vitro experiments employing the RAW264 cell line and primary bone marrow cells with selective p38 inhibitors and dominant negative forms of p38 signaling components. [46][47][48] In those cells, p38a functions downstream of RANK after stimulation by RANKL (the proresorptive cytokine that is necessary and sufficient for osteoclastogenesis) to stimulate osteoclast formation, maturation and bone resorption 46,47 (Figure 3).…”

“…47 Consistent with those data, mice with post-developmental deletion of the p38a-encoding gene under the control of the inducible Mx1 promoter display reduced osteoclast number, low bone resorption and increased bone mass under physiological conditions, and are protected against TNF-a-induced arthritis and systemic bone loss. 45 Although the Mx1-cre deleter strain is known to induce complete gene excisions in hepatocytes and hematopoietic cells, and variable deletions in other cell types, 49 this decreased osteoclastogenesis has been shown to be cell autonomous, as bone marrow hematopoietic cells lacking p38a cannot differentiate into mature osteoclasts in response to macrophage colonystimulating factor (M-CSF) and RANKL treatment in vitro. 45 MKK3 and MKK6 have been found to be required for osteoclastogenesis in vitro.…”

“…45 Although the Mx1-cre deleter strain is known to induce complete gene excisions in hepatocytes and hematopoietic cells, and variable deletions in other cell types, 49 this decreased osteoclastogenesis has been shown to be cell autonomous, as bone marrow hematopoietic cells lacking p38a cannot differentiate into mature osteoclasts in response to macrophage colonystimulating factor (M-CSF) and RANKL treatment in vitro. 45 MKK3 and MKK6 have been found to be required for osteoclastogenesis in vitro. 37,46,50 In accordance with this, both Mkk3 À / À and Mkk6 À / À mice exhibit a higher trabecular bone mass with increased trabecular number and decreased trabecular spacing in comparison with control littermates at 4 months of age.…”

Manganese overload affects p38 MAPK phosphorylation and metalloproteinase activity during sea urchin embryonic development

“…Lately it has been demonstrated that p38 MAPK signaling is essential for skeletogenesis and bone homeostasis in mice (Greenblatt et al, 2010;Thouverey and Caverzasio, 2012). However, it has been shown that an over increase of p38 MAPK phosphorylation contributed to potentiation of osteoclastogenesis, and arthritic bone loss (Karsdal et al, 2003;Böhm et al, 2013). The activation of MAPK proteins, through the combined activities of the matrix-degrading MMPs, such as MMP2, MMP7 and MMP9, has been observed in osteoarthritic-cartilage-damage human models (Malemud, 2006;Ding et al, 2010).…”