Protein Phosphatase PP5 Controls Bone Mass and the Negative Effects of Rosiglitazone on Bone through Reciprocal Regulation of PPARγ (Peroxisome Proliferator-activated Receptor γ) and RUNX2 (Runt-related Transcription Factor 2).
Peroxisome proliferator-activated receptor γ (PPARγ) and runt-related transcription factor 2 (RUNX2) are key regulators of mesenchymal stem cell (MSC) differentiation toward adipocytes and osteoblasts, respectively. Post-translational modifications of these factors determine their activities. Dephosphorylation of PPARγ at Ser-112 is required for its adipocytic activity, whereas phosphorylation of RUNX2 at serine 319 (Ser-319) promotes its osteoblastic activity. Here we show that protein phosphatase 5 (PP5) reciprocally regulates each receptor by targeting each serine. Mice deficient in PP5 phosphatase have increased osteoblast numbers and high bone formation, which results in high bone mass in the appendicular and axial skeleton. This is associated with a substantial decrease in lipid-containing marrow adipocytes. Indeed, in the absence of PP5 the MSC lineage allocation is skewed toward osteoblasts and away from lipid accumulating adipocytes, although an increase in beige adipocyte gene expression is observed. In the presence of rosiglitazone, PP5 translocates to the nucleus, binds to PPARγ and RUNX2, and dephosphorylates both factors, resulting in activation of PPARγ adipocytic and suppression of RUNX2 osteoblastic activities. Moreover, shRNA knockdown of PP5 results in cells refractory to rosiglitazone treatment. Lastly, mice deficient in PP5 are resistant to the negative effects of rosiglitazone on bone, which in wild type animals causes a 50% decrease in trabecular bone mass. In conclusion, PP5 is a unique phosphatase reciprocally regulating PPARγ and RUNX2 activities in marrow MSC.
From the Department of Orthopaedic Surgery,; the Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, Ohio 43614 and.
Lance A
LA
Stechschulte
the Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109.
Chunxi
C
Ge
Physiology and Pharmacology, and.
Terry D
TD
Hinds
the Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, Ohio 43614 and; Physiology and Pharmacology, and.
Edwin R
ER
Sanchez
the Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109.
Renny T
RT
Franceschi
From the Department of Orthopaedic Surgery,; the Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, Ohio 43614 and; Physiology and Pharmacology, and. Electronic address: beata.leckaczernik@utoledo.edu.
Beata
B
Lecka-Czernik
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000187:drug effects* / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D050659:Core Binding Factor Alpha 1 Subunit; D006023:Glycoproteins; D047495:PPAR gamma; C493716:Runx2 protein, mouse; D045162:Thiazolidinediones; C021240:tissue-factor-pathway inhibitor 2; D000077154:Rosiglitazone
adipocyte; bone; chaperone; mesenchymal stem cells (MSCs); osteoblast; osteocyte; peroxisome proliferator-activated receptor (PPAR); protein phosphatase
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