Apoptosis of Bone Cells

Jilka, Robert L.; Bellido, Teresita; Almeida, Maria; Plotkin, Lilian I.; O’Brien, Charles A.; Weinstein, Robert S.; Manolagas, Stavros C.

doi:10.1016/b978-0-12-373884-4.00032-x

Cited by 22 publications

(23 citation statements)

References 216 publications

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“…In contrast, GSIXX only partially prevented MLO-A5 cell death measured at 48h, suggesting that factors secreted by MM cells accumulated during culture contribute to osteocyte apoptosis at later time points. In support of this notion, levels of TNFα, a recognized inducer of osteoblast and osteocyte apoptosis (31), increased 4-fold from 4 to 48h in CM from JJN3 cell cultures (Figure 3D), and addition of TNFα increased MLO-A5 cell death (Suppl. Figure 1G).…”

Section: Resultsmentioning

confidence: 57%

“…Thus, whereas activation of Notch signaling protects several cancer cell types from apoptosis (36, 41), it induces apoptosis of neural progenitor cells (42), CD34 + hematopoietic stem/progenitor cells (43), and osteocytes (this report). Similarly, activation of canonical Wnt signaling inhibits apoptosis in different cells of the osteoblastic lineage (31, 44), whereas it increases apoptosis in hematopoietic stem/progenitor cells (45) or in melanoma cells (46). These findings show that the same signaling pathway can elicit different biological responses depending on the ligands/signals present in a particular microenvironment, the receptor repertoire exhibited by the target cell, and the intracellular machinery that integrates extracellular cues and transduces them into biological outcomes.…”

Section: Discussionmentioning

confidence: 99%

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Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

et al. 2016

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In multiple myeloma (MM) increased numbers of monoclonal plasma cells in the bone marrow induce localized osteolytic lesions that rarely heal, due to increased bone resorption and suppressed bone formation. Numerous studies reported the contributions that different cell types in the MM microenvironment make to MM growth and bone disease, but the role of matrix-embedded osteocytes in MM, which comprise >95% of bone cells and are major regulators of osteoclast and osteoblast activity, is unclear. We report that osteocytes in MM-bearing bones physically interact with MM cells in vivo, undergo caspase3-dependent apoptosis, and express higher RANKL and Sclerostin levels than osteocytes from control mice. Mechanistic studies revealed that osteocyte apoptosis is initiated by activation of Notch signaling in osteocytes through direct contact with MM cells, and is further amplified by MM cell-secreted TNFα. This Notch/TNFα induced osteocyte apoptosis increases osteocytic Rankl expression, the osteocytic Rankl/Opg ratio and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Further, osteocytes in contact with MM cells express high levels of Sost/Sclerostin that decrease Wnt signaling in osteoblasts and inhibit osteoblast differentiation. Importantly, direct contact between osteocytes and MM cells reciprocally activates Notch signaling and increases Notch receptor expression in MM cells, in particular Notch3 and 4, and stimulates MM cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling between MM cells and osteocytes that enhances MM growth and bone disease, and suggest the potential of targeting osteocyte-MM cell interactions as a novel MM treatment.

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Section: Resultsmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

et al. 2016

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“…Osteocyte viability is a determinant of bone strength, and it is diminished in several pathologies associated with bone loss and bone fragility, including aging, loss of sex steroids, and glucocorticoid excess (38). Physiological levels of mechanical force, such as those provided by normal ambulatory activity or moderate physical exercise, are critical to maintain osteocyte viability by mechanisms still unclear.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between Caveolin-1/Extracellular Signal-regulated Kinase (ERK) and β-Catenin Survival Pathways in Osteocyte Mechanotransduction

Gortázar

Martin-Millan

Bravo

et al. 2013

Journal of Biological Chemistry

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Background: Mechanical stimulation prevents osteocyte apoptosis and activates Wnt signaling. Results: ERK-mediated anti-apoptosis is abolished by antagonists of Wnt signaling, and conversely, ␤-catenin accumulation is blocked by inhibiting the caveolin-1/ERK pathway. Conclusion: Caveolin-1/ERK and Wnt/␤-catenin signaling pathways cooperate in transducing mechanical cues into osteocyte survival. Significance: This novel bidirectional crosstalk might be targeted to increase bone strength by preserving osteocyte viability.

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“…The cause of this spontaneous apoptosis remains unknown. It is believed that apoptosis is the default fate for all nucleated cells and only cells that have active survival signals remain alive [15]. For example, inhibition of osteocyte apoptosis by deletion of the pro-apoptotic proteins Bak and Bax generates dysfunctional osteocytes [16].…”

Section: Why Osteocytes Die?mentioning

confidence: 99%

Apoptotic Osteocytes and the Control of Targeted Bone Resorption

Plotkin

2014

Curr Osteoporos Rep

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Studies from the 1950s and 1960s already recognize the fact that osteocytes, although long living cells, die, as evidenced by accumulation of osteocytic lacunae devoid of cells. More recently, it was demonstrated that these cells die by apoptosis. The rate of osteocyte apoptosis is regulated by the age of the bone, as well as by systemic hormones, local growth factors, cytokines, pharmacological agents, and mechanical forces. Apoptotic osteocytes, in turn, recruit osteoclasts to initiate targeted bone resorption. This results in the removal of “dead” bone and may improve the mechanical properties of the skeleton. However, the molecular regulators of osteocyte survival and targeted bone remodeling are not completely known. In this review, the current knowledge on the molecular mechanism that lead to osteocyte death or survival, and the signals that mediate targeted bone resorption is discussed.

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Apoptosis of Bone Cells

Cited by 22 publications

References 216 publications

Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Crosstalk between Caveolin-1/Extracellular Signal-regulated Kinase (ERK) and β-Catenin Survival Pathways in Osteocyte Mechanotransduction

Apoptotic Osteocytes and the Control of Targeted Bone Resorption

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