FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells

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.

show abstract

“…This assays were performed as previously described (21). Detailed description of the assay can be found in Supplementary Methods.…”

Section: Methodsmentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Gene expression was analyzed using the TATA box-binding protein as a housekeeping gene, as described before (26,27). Earlier published work demonstrates the functionality of Ots in these bone organ cultures (11,19,20,28,29).…”

Section: Ex Vivo Experimentsmentioning

confidence: 99%

MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production

et al. 2018

View full text Add to dashboard Cite

Parathyroid hormone (PTH) affects the skeleton by acting on osteocytes (Ots) in bone through yet unclear mechanisms. We report that matrix metalloproteinase 14 (MMP14) expression/activity are increased in bones from mice with genetic constitutive activation (ca) of the PTH receptor 1 (PTH1R) in Ots (caPTH1R) and in bones from mice exposed to elevated PTH levels but not in mice lacking [conditional knockout (cKO)] the PTH1R in Ots (cKOPTH1R). Furthermore, PTH upregulates MMP14 in human bone cultures and in Ot-enriched bones from floxed control mice but not from cKOPTH1R mice. MMP14 activity increases soluble receptor activator of NF-κΒ ligand production, which in turn, stimulates osteoclast differentiation and resorption. Pharmacologic inhibition of MMP14 activity reduced the high bone remodeling exhibited by caPTH1R mice or induced by chronic PTH elevation and decreased bone resorption but allowed full stimulation of bone formation induced by PTH injections, thereby potentiating bone gain. Thus, MMP14 is a new member of the intricate gene network activated in Ots by PTH1R signaling that can be targeted to adjust the skeletal responses to PTH in favor of bone preservation.-Delgado-Calle, J., Hancock, B., Likine, E. F., Sato, A. Y., McAndrews, K., Sanudo, C., Bruzzaniti, A., Riancho, J. A., Tonra, J. R., Bellido, T. MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production.

show abstract

“…In addition to these results, recent findings suggest that FGF23 derived from osteocytes drives MM growth in bone by binding to FGF23 receptors and the co-receptor Klotho in MM cells, and activating transcription of pro-metastatic and pro-osteolytic genes, such as heparanase (93). Furthermore, osteocytes located in osteolytic lesions in MM patients overproduce interleukin 11 (IL-11), which is sufficient to enhance osteoclast differentiation (90).…”

Section: Osteocytes and Bone Remodeling Under Pathological Conditionsmentioning

confidence: 91%

Osteocytes and Skeletal Pathophysiology

Delgado‐Calle

Bellido

2015

Curr Mol Bio Rep

View full text Add to dashboard Cite

For many years, osteocytes have been the forgotten bone cells and considered as inactive spectators buried in the bone matrix. We now know that osteocytes detect and respond to mechanical and hormonal stimuli to coordinate bone resorption and bone formation. Osteocytes are currently considered a major source of molecules that regulate the activity of osteoclasts and osteoblasts, such as RANKL and sclerostin; and genetic and pharmacological manipulations of either molecule markedly affect bone homeostasis. Besides playing a role in physiological bone homeostasis, accumulating evidence supports the notion that dysregulation of osteocyte function and alteration of osteocyte life-span underlies the pathophysiology of skeletal disorders characterized by loss bone mass and increased bone fragility, as well as the damaging effects of cancer in bone. In this review, we highlight some of these investigations and discuss novel observations that demonstrate that osteocytes, far from being passive cells entombed in the bone, are critical for bone function and maintenance.

show abstract

FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells

Cited by 41 publications

References 54 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

MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production

Osteocytes and Skeletal Pathophysiology

Contact Info

Product

Resources

About