Multiple myeloma–derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

Liang

J of Cellular Biochemistry

et al. 2018

Osteoclasts are multinuclear giant cells responsible for bone resorption in bone loss diseases, including rheumatoid arthritis, periodontitis, and the aseptic loosening of orthopedic implants. Because of injurious side effects with currently available drugs, it is necessary to continue research novel bone‐protective therapies. Daidzin, a naturally occurring isoflavone found in leguminous plants, has numerous beneficial pharmacologic effects, including anti‐cancer, anti‐cholesterol, and anti‐angiocardiopathy, promoting osteoblasts differentiation, and even anti‐osteoporosis. However, the effect of daidzin on the regulation of osteoclast activity has not yet been investigated. In this study, our study showed that daidzin significantly inhibited receptor activator of nuclear factor‐kB ligand (RANKL)‐induced osteoclast differentiation of bone marrow macrophages and the hydroxyapatite‐resorbing activity of mature osteoclasts by inhibiting RANKL‐induced NF‐kB signaling pathway. In addition, daidzin could inhibit the expression of osteoclast marker genes, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), cellular oncogene fos (c‐Fos), tartrate‐resistant acid phosphatase (TRAP), and cathepsin K (CTSK). Consistent with in vitro results, daidzin inhibited lipopolysaccharide‐induced bone loss by suppressing the osteoclast differentiation. Together our data demonstrated that daidzin inhibits RANKL‐induced osteoclastogenesis through suppressing NF‐ĸB signaling pathway and that daidzin is a promising agent in the treatment of osteolytic diseases.

Section: Discussionmentioning

confidence: 99%

Retracted: Daidzin inhibits RANKL‐induced osteoclastogenesis in vitro and prevents LPS‐induced bone loss in vivo

Liang

J of Cellular Biochemistry

et al. 2018

“…Consistent with this evidence, NF‐κB activity was increased in osteoprogenitors; and SASP components such as TNF‐α, MMP13, CXCL12, and IL‐1α were also elevated. All these proteins have osteoclastogenic properties (Pfeilschifter et al ., ; Wright et al ., ; Fu et al ., ) and most probably contributed, along with RANKL, to the increased osteoclast formation seen in co‐cultures with stromal cells from old mice. Support for the contention that senescent cells contribute to osteoclastogenesis is provided by the findings that senescent osteoblastic cells, resulting from overexpression of the cyclin inhibitor p27KIP1, increase osteoclast formation in a co‐culture system in vitro and osteoclasts number in vivo (Luo et al ., ).…”

Section: Discussionmentioning

confidence: 99%

DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age

et al. 2017

SummaryAge‐related bone loss in mice results from a decrease in bone formation and an increase in cortical bone resorption. The former is accounted by a decrease in the number of postmitotic osteoblasts which synthesize the bone matrix and is thought to be the consequence of age‐dependent changes in mesenchymal osteoblast progenitors. However, there are no specific markers for these progenitors, and conclusions rely on results from in vitro cultures of mixed cell populations. Moreover, the culprits of such changes remain unknown. Here, we have used Osx1‐Cre;TdRFP mice in which osteoprogenitors express the TdRFP fluorescent protein. We report that the number of TdRFP‐Osx1 cells, freshly isolated from the bone marrow, declines by more than 50% between 6 and 24 months of age in both female and male mice. Moreover, TdRFP‐Osx1 cells from old mice exhibited markers of DNA damage and senescence, such as γH2AX foci, G1 cell cycle arrest, phosphorylation of p53, increased p21CIP 1 levels, as well as increased levels of GATA4 and activation of NF‐κB – two major stimulators of the senescence‐associated secretory phenotype (SASP). Bone marrow stromal cells from old mice also exhibited elevated expression of SASP genes, including several pro‐osteoclastogenic cytokines, and increased capacity to support osteoclast formation. These changes were greatly attenuated by the senolytic drug ABT263. Together, these findings suggest that the decline in bone mass with age is the result of intrinsic defects in osteoprogenitor cells, leading to decreased osteoblast numbers and increased support of osteoclast formation.

“…For instance, the over-expression of MMP-9 promotes vascular invasion and is closely related to the bone destruction and metastasis of GCTB. MMP-13 is able to degrade interstitial collagen during tumor invasion and metastasis, and stimulate osteoclast differentiation [42]. RANKL expression is closely related to epithelial-to-mesenchymal transition (EMT), and PTHrP could regulate bone development and mineral homeostasis by enhancing the production of RANKL and MMP-13 [43].…”

Section: Discussionmentioning

confidence: 99%

Molecular and cellular mechanisms for zoledronic acid-loaded magnesium-strontium alloys to inhibit giant cell tumors of bone

Wang

Zhu

et al. 2018

Acta Biomaterialia

In clinics, giant cell tumors of bone (GCTB) are removed by surgery. However, the resultant defects in bone still contain aggressive and metastatic GCTB cells that can recruit osteoclasts to damage bone, leading to new GCTB tumor growth and bone damage after tumor surgery. Hence, it is of high demand in developing a material that can not only fill the bone defects as an implant but also inhibit GCTB in the defect area as a therapeutic agent. More importantly, the molecular and cellular mechanism by which such a material inhibits GCTB growth has never been explored. To solve these two problems, we prepared a new biomaterial, the Mg-Sr alloys that were first coated with calcium phosphate and then loaded with a tumor-inhibiting molecule (Zoledronic acid, ZA). Then, by using a variety of molecular and cellular biological assays, we studied how the ZA-loaded alloys induced the death of GCTB cells (derived from patients) and inhibited their growth at the molecular and cellular level. At the cellular level, our results showed that ZA-loaded Mg-Sr alloys not only induced apoptosis and oxidative stress of GCTB cells, and suppressed their induced pre-osteoclast recruitment, but also inhibited their migration. At the molecular level, our data showed that ZA released from the ZA-loaded Mg-Sr alloys could significantly activate the mitochondrial pathway and inhibit the NF-κB pathway in the GCTB cells. Both mechanisms collectively induced GCTB cell death and inhibited GCTB cell growth. This work showed how a biomaterial inhibit tumor growth at the molecular and cellular level, increasing our understanding in the fundamental principle of materials-induced cancer therapy. This work will be interesting to readers in the fields of metallic materials, inorganic materials, biomaterials and cancer therapy.