PXD020832

PXD020832 is an original dataset announced via ProteomeXchange.

Title	Compound Deletion of Thrombospondin-1 and -2 Results in a Skeletal Phenotype not Predicted by the Single Gene Knockouts
Description	The trimeric thrombospondin homologs, TSP1 and TSP2, are both components of bone tissue and contribute in redundant and distinct ways to skeletal physiology. The functional effects of combined TSP1 and TSP2 deficiency remain to be elucidated. Here, we examined the spectrum of detergent soluble proteins in diaphyseal cortical bone of growing (6-week old) male and female mice deficient in both thrombospondins (double knockout (DKO)). Equal amounts of detergent soluble cortical bone protein were subject to Tandem Mass Tags (TMT) quantitative proteomics. 3,429 proteins met the selection criteria (FDR≤ 1% and 2 peptide spectral matches). 181 proteins were differentially abundant in both male and female DKO bones (≥1.95 fold or ≤0.55 fold compared to wild-type). Physiologically relevant annotation terms identified by Ingenuity Pathway Analysis included “ECM degradation” and “Quantity of Monocytes.” Manual inspection revealed that a number of proteins with shared expression among osteoclasts and osteocytes were reduced in DKO bones. To associate changes in protein content with phenotype, we examined 12-week old male DKO and WT mice. DKO mice were smaller than WT. DKO femora had reduced cross-sectional area with a flattened, less circular cross-section. DKO bones were less stiff in bending, but this reduction was disproportionate to the decreases in bending moment of inertia on nanoCT leading to a modest increase in predicted modulus (stiffness/bending moment). DKO displayed a lower ultimate load along with increases in both ultimate displacement and yield displacement. The ratio of ultimate displacement to yield displacement was actually higher in DKO, suggesting that decreased yield displacement does not account entirely for the reduction in ultimate displacement. Together, these mechanical attributes suggest compensation for small bone size through mechanisms that are not explained by nanoCT structural analysis. DKO mice also exhibited reductions in trabecular bone mass, which were surprisingly associated with increased osteoblast numbers and osteoid surface. Marrow-derived colony forming unit-fibroblastic was reduced in DKO mice. Together our data suggest that when both TSP1 and TSP2 are absent, a unique bone phenotype not predicted by the single knockouts, is manifested
HostingRepository	PRIDE
AnnounceDate	2021-08-26
AnnouncementXML	Submission_2021-08-26_08:03:49.708.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andrea Alford
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-10 14:23:28	ID requested
⏵ 1	2021-08-26 08:03:50	announced

Alford AI, Stephan C, Kozloff KM, Hankenson KD, Compound deletion of thrombospondin-1 and -2 results in a skeletal phenotype not predicted by the single gene knockouts. Bone, 153():116156(2021) [pubmed]

submitter keyword: Thrombospondins, bone, osteoblasts, osteoclasts

Andrea Alford
contact affiliation	Department of Orthopaedic Surgery, University of Michigan School of Medicine, A. Alfred Taubman Biomedical Sciences Research Building, Room 2009, Ann Arbor, MI, 48109
contact email	aialford@umich.edu
lab head
Andrea Alford
contact affiliation	University of Michigan
contact email	aialford@umich.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD020832
     1. Label: PRIDE project
     2. Name: Compound Deletion of Thrombospondin-1 and -2 Results in a Skeletal Phenotype not Predicted by the Single Gene Knockouts