Serine/threonine phosphatases in osteoclastogenesis and bone resorption

Karkache, Ismael Y.; Damodaran, Jeyaram R.; Molstad, David H. H.; Bradley, Elizabeth W.

doi:10.1016/j.gene.2020.145362

Cited by 13 publications

(14 citation statements)

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“…PH Domain and Leucine Rich Repeat Protein Phosphatase 1 (Phlpp1, Phlpp, Scop, Plekhe1, Ppm3a) is a serine/threonine protein phosphatase. Phlpp1 and its related isoform, Phlpp2, are metal-dependent type 2C protein phosphatases [ 1 , 2 ] that are insensitive to traditional phosphatase inhibitors [ 1 ]. Phlpp1 is broadly expressed, but its levels are controlled by numerous cellular mechanisms, and decline with age in women [ 1 , 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Phlpp1 and its related isoform, Phlpp2, are metal-dependent type 2C protein phosphatases [ 1 , 2 ] that are insensitive to traditional phosphatase inhibitors [ 1 ]. Phlpp1 is broadly expressed, but its levels are controlled by numerous cellular mechanisms, and decline with age in women [ 1 , 2 , 3 ]. Our prior work also demonstrates that Phlpp1 levels are increased by estradiol in vitro [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…PHLPP1 dephosphorylates and inactivates several kinases that regulate osteoclastogenesis and bone resorption including Akt, a kinase that is well established in promoting osteoclast differentiation, survival, and activity [ 5 ]. PHLPP1 catalyzes the dephosphorylation of AktS473, the site within the activation loop that is required for maximal Akt activity [ 2 , 6 ]. In addition to Akt, numerous PKC isoforms that promote osteoclast function are also inactivated and destabilized by PHLPP1-mediated dephosphorylation [ 2 , 7 , 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…PHLPP1 catalyzes the dephosphorylation of AktS473, the site within the activation loop that is required for maximal Akt activity [ 2 , 6 ]. In addition to Akt, numerous PKC isoforms that promote osteoclast function are also inactivated and destabilized by PHLPP1-mediated dephosphorylation [ 2 , 7 , 8 , 9 , 10 , 11 ]. PHLPP1 also targets the pro-apoptotic Mst1 to limit cell survival and the ribosomal kinase p70 S6K to control the rate of CAP-dependent translation [ 9 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Myeloid Lineage Ablation of Phlpp1 Regulates M-CSF Signaling and Tempers Bone Resorption in Female Mice

Karkache

Damodaran

Molstad

et al. 2021

IJMS

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Prior work demonstrated that Phlpp1 deficiency alters trabecular bone mass and enhances M-CSF responsiveness, but the cell types and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within myeloid lineage cells, we crossed Phlpp1 floxed mice with mice harboring LysM-Cre. Micro-computed tomography of the distal femur of 12-week-old mice revealed a 30% increase in bone volume per total volume of Phlpp1 female conditional knockouts, but we did not observe significant changes within male Phlpp1 cKOLysM mice. Bone histomorphmetry of the proximal tibia further revealed that Phlpp1 cKOLysM females exhibited elevated osteoclast numbers, but conversely had reduced levels of serum markers of bone resorption as compared to littermate controls. Osteoblast number and serum markers of bone formation were unchanged. In vitro assays confirmed that Phlpp1 ablation enhanced osteoclast number and area, but limited bone resorption. Additionally, reconstitution with exogenous Phlpp1 suppressed osteoclast numbers. Dose response assays demonstrated that Phlpp1−/− cells are more responsive to M-CSF, but reconstitution with Phlpp1 abrogated this effect. Furthermore, small molecule-mediated Phlpp inhibition enhanced osteoclast numbers and size. Enhanced phosphorylation of Phlpp substrates—including Akt, ERK1/2, and PKCζ—accompanied these observations. In contrast, actin cytoskeleton disruption occurred within Phlpp inhibitor treated osteoclasts. Moreover, Phlpp inhibition reduced resorption of cells cultured on bovine bone slices in vitro. Our results demonstrate that Phlpp1 deficiency within myeloid lineage cells enhances bone mass by limiting bone resorption while leaving osteoclast numbers intact; moreover, we show that Phlpp1 represses osteoclastogenesis and controls responses to M-CSF.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Myeloid Lineage Ablation of Phlpp1 Regulates M-CSF Signaling and Tempers Bone Resorption in Female Mice

Karkache

Damodaran

Molstad

et al. 2021

IJMS

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“…Bone is a highly mineralized structure constituting the body skeleton, which performs functions ranging from support to locomotion and posture to protection of the main internal organs and brain. Bone is also essential for hematopoiesis, ensured by cells present in the marrow inside bones, as well as for the storage of minerals, the function of which is regulated by factors produced within bone itself such as growth factors and hormones (i.e., bone morphogenetic proteins and calcitonin, respectively) [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

In Search of a Role for Extracellular Purine Enzymes in Bone Function

et al. 2021

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Bone is one of the major tissues that undergoes continuous remodeling throughout life, thus ensuring both organic body growth during development and protection of internal organs as well as repair of trauma during adulthood. Many endogenous substances contribute to bone homeostasis, including purines. Their role has increasingly emerged in recent decades as compounds which, by interacting with specific receptors, can help determine adequate responses of bone cells to physiological or pathological stimuli. Equally, it is recognized that the activity of purines is closely dependent on their interconversion or metabolic degradation ensured by a series of enzymes present at extracellular level as predominantly bound to the cell membrane or, also, as soluble isoforms. While the effects of purines mediated by their receptor interactions have sufficiently, even though not entirely, been characterized in many tissues including bone, those promoted by the extracellular enzymes providing for purine metabolism have not been. In this review, we will try to circumstantiate the presence and the role of these enzymes in bone to define their close relationship with purine activities in maintaining bone homeostasis in normal or pathological conditions.

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Phlpp1 Expression in Osteoblasts Plays a Modest Role in Bone Homeostasis

Karkache,

Molstad,

et al. 2023

JBMR Plus

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Prior work demonstrated that Phlpp1 deficiency alters limb length and bone mass, but the cell types involved and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within bone‐forming osteoblasts, we crossed Phlpp1 floxed mice with mice harboring type 1 collagen (Col1a12.3kb)‐Cre. Mineralization of bone marrow stromal cell cultures derived from Phlpp1 cKOCol1a1 was unchanged, but levels of inflammatory genes (eg, Ifng, Il6, Ccl8) and receptor activator of NF‐κB ligand/osteoprotegerin (RANKL/OPG) ratios were enhanced by either Phlpp1 ablation or chemical inhibition. Micro‐computed tomography of the distal femur and L5 vertebral body of 12‐week‐old mice revealed no alteration in bone volume per total volume, but compromised femoral bone microarchitecture within Phlpp1 cKOCol1a1 conditional knockout females. Bone histomorphometry of the proximal tibia documented no changes in osteoblast or osteoclast number per bone surface but slight reductions in osteoclast surface per bone surface. Overall, our data show that deletion of Phlpp1 in type 1 collagen–expressing cells does not significantly alter attainment of peak bone mass of either males or females, but may enhance inflammatory gene expression and the ratio of RANKL/OPG. Future studies examining the role of Phlpp1 within models of advanced age, inflammation, or osteocytes, as well as functional redundancy with the related Phlpp2 isoform are warranted. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Serine/threonine phosphatases in osteoclastogenesis and bone resorption

Cited by 13 publications

References 135 publications

Myeloid Lineage Ablation of Phlpp1 Regulates M-CSF Signaling and Tempers Bone Resorption in Female Mice

Myeloid Lineage Ablation of Phlpp1 Regulates M-CSF Signaling and Tempers Bone Resorption in Female Mice

In Search of a Role for Extracellular Purine Enzymes in Bone Function

Phlpp1 Expression in Osteoblasts Plays a Modest Role in Bone Homeostasis

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