Bone morphogenetic proteins: Their role in regulating osteoclast differentiation

Huntley, Raphael; Jensen, Eric D.; Gopalakrishnan, Rajaram; Mansky, Kim C.

doi:10.1016/j.bonr.2019.100207

Cited by 39 publications

(34 citation statements)

References 101 publications

(161 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that in BMP signaling transduction, the choice of whether the SMAD or non-SMAD signaling pathway should be activated depends on the way in which BMP binds to the receptor complex. If BMP binds to a preformed BMP receptor type I/BMP receptor type II complex, the SMAD signaling pathway is expressed [ 88 ]. On the other hand, if BMP binds to BMP receptor type 1 or BMP receptor type II to recruit the other, the non-SMAD signaling pathway is expressed [ 71 , 89 ].…”

Section: Discussionmentioning

confidence: 99%

A Synthetic Peptide, CK2.3, Inhibits RANKL-Induced Osteoclastogenesis through BMPRIa and ERK Signaling Pathway

Nguyen

Kelly

Wood

et al. 2020

JDB

View full text Add to dashboard Cite

The skeletal system plays an important role in the development and maturation process. Through the bone remodeling process, 10% of the skeletal system is renewed every year. Osteoblasts and osteoclasts are two major bone cells that are involved in the development of the skeletal system, and their activity is kept in balance. An imbalance between their activities can lead to diseases such as osteoporosis that are characterized by significant bone loss due to the overactivity of bone-resorbing osteoclasts. Our laboratory has developed a novel peptide, CK2.3, which works as both an anabolic and anti-resorptive agent to induce bone formation and prevent bone loss. We previously reported that CK2.3 mediated mineralization and osteoblast development through the SMAD, ERK, and AKT signaling pathways. In this study, we demonstrated the mechanism by which CK2.3 inhibits osteoclast development. We showed that the inhibition of MEK by the U0126 inhibitor rescued the osteoclast development of RAW264.7 induced by RANKL in a co-culture system with CK2.3. We observed that CK2.3 induced ERK activation and BMPRIa expression on Day 1 after stimulation with CK2.3. While CK2.3 was previously reported to induce the SMAD signaling pathway in osteoblast development, we did not observe any changes in SMAD activation in osteoclast development with CK2.3 stimulation. Understanding the mechanism by which CK2.3 inhibits osteoclast development will allow CK2.3 to be developed as a new treatment for osteoporosis.

show abstract

Section: Discussionmentioning

confidence: 99%

A Synthetic Peptide, CK2.3, Inhibits RANKL-Induced Osteoclastogenesis through BMPRIa and ERK Signaling Pathway

Nguyen

Kelly

Wood

et al. 2020

JDB

View full text Add to dashboard Cite

show abstract

“…BMP has been reported to affect osteoclastogenesis indirectly and directly as well as exert osteoinductive effects on bone formation. 20,21 In this study, rhBMP2-induced ectopic bone in Smurf2 −/− mice exhibited increases in the TRAP-positive area and number of osteoclasts. In vitro, Smurf2 −/− BMSCs showed enhanced Rankl expression when cultured in rhBMP2-supplemented medium.…”

Section: Smurf2mentioning

confidence: 51%

A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone

et al. 2020

View full text Add to dashboard Cite

Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) play important roles in bone metabolism. Smad ubiquitination regulatory factors (Smurfs) regulate TGF-β/BMP signaling via ubiquitination, resulting in degradation of signaling molecules to prevent excessive activation of TGF-β/BMP signaling. Though Smurf2 has been shown to negatively regulate TGF-β/Smad signaling, its involvement in BMP/Smad signaling in bone metabolism has not been thoroughly investigated. In the present study, we sought to evaluate the role of Smurf2 in BMP/Smad signaling in bone metabolism. Absorbable collagen sponges containing 3 μg of recombinant human BMP2 (rhBMP2) were implanted in the dorsal muscle pouches of wild type (WT) and Smurf2−/− mice. The rhBMP2-induced ectopic bone in Smurf2−/− mice showed greater bone mass, higher mineral apposition and bone formation rates, and greater osteoblast numbers than the ectopic bone in WT mice. In WT mice, the ectopic bone consisted of a thin discontinuous outer cortical shell and scant inner trabecular bone. In contrast, in Smurf2−/− mice, the induced bone consisted of a thick, continuous outer cortical shell and abundant inner trabecular bone. Additionally, rhBMP2-stimulated bone marrow stromal cells (BMSCs) from Smurf2−/− mice showed increased osteogenic differentiation. Smurf2 induced the ubiquitination of Smad1/5. BMP/Smad signaling was enhanced in Smurf2−/− BMSCs stimulated with rhBMP2, and the inhibition of BMP/Smad signaling suppressed osteogenic differentiation of these BMSCs. These findings demonstrate that Smurf2 negatively regulates BMP/Smad signaling, thereby identifying a new regulatory mechanism in bone metabolism.

show abstract

“…Osteoblastic lesions arise from cancer-induced signalling via bone morphogenetic proteins (BMPs), fibroblast growth factor and TGFβ resulting in osteoblast activation [ 24 ]. Expression of BMP-2, -4, -6 and -7 is elevated within bone metastases [ 33 ] within which BMPs can induce the osteogenic differentiation of osteoblasts [ 34 ].…”

Section: Bone Homeostasis and The Vicious Cyclementioning

confidence: 99%

Personal Medicine and Bone Metastases: Biomarkers, Micro-RNAs and Bone Metastases

Wood¹,

Brown

2020

Cancers

View full text Add to dashboard Cite

Bone metastasis is a major cause of morbidity within solid tumours of the breast, prostate, lung and kidney. Metastasis to the skeleton is associated with a wide range of complications including bone fractures, spinal cord compression, hypercalcaemia and increased bone pain. Improved treatments for bone metastasis, such as the use of anti-bone resorptive bisphosphonate agents, within post-menopausal women have improved disease-free survival; however, these treatments are not without side effects. There is thus a need for biomarkers, which will predict the risk of developing the spread to bone within these cancers. The application of molecular profiling techniques, together with animal model systems and engineered cell-lines has enabled the identification of a series of potential bone-metastasis biomarker molecules predictive of bone metastasis risk. Some of these biomarker candidates have been validated within patient-derived samples providing a step towards clinical utility. Recent developments in multiplex biomarker quantification now enable the simultaneous measurement of up to 96 micro-RNA/protein molecules in a spatially defined manner with single-cell resolution, thus enabling the characterisation of the key molecules active at the sites of pre-metastatic niche formation as well as tumour-stroma signalling. These technologies have considerable potential to inform biomarker discovery. Additionally, a potential future extension of these discoveries could also be the identification of novel drug targets within cancer spread to bone. This chapter summarises recent findings in biomarker discovery within the key bone metastatic cancers (breast, prostate, lung and renal cell carcinoma). Tissue-based and circulating blood-based biomarkers are discussed from the fields of genomics, epigenetic regulation (micro-RNAs) and protein/cell-signalling together with a discussion of the potential future development of these markers towards clinical development.

show abstract

Bone morphogenetic proteins: Their role in regulating osteoclast differentiation

Cited by 39 publications

References 101 publications

A Synthetic Peptide, CK2.3, Inhibits RANKL-Induced Osteoclastogenesis through BMPRIa and ERK Signaling Pathway

A Synthetic Peptide, CK2.3, Inhibits RANKL-Induced Osteoclastogenesis through BMPRIa and ERK Signaling Pathway

A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone

Personal Medicine and Bone Metastases: Biomarkers, Micro-RNAs and Bone Metastases

Contact Info

Product

Resources

About