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SHP-1 Protein Tyrosine Phosphatase Affects Early Postnatal Bone Development in Mice

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Abstract

The Src homology region 2 domain-containing phosphatase-1 (SHP-1) is an intracellular tyrosine phosphatase that plays a negative regulatory role in immune cell signaling. Absent or diminished SHP-1 catalytic activity results in reduced bone mass with enhanced bone resorption. Here, we sought to investigate if Shp1 overexpression leads to increased bone mass and improved mechanical properties. Male and female wildtype (WT) and SHP1-transgenic (Tg) mice at 28, 56, and 84 days of age were compared. We applied microcomputed tomography to assess femoral cortical bone geometry and trabecular architecture and 3-point mechanical bending to assess mid-diaphyseal structural and estimated material properties. Serum OPG, RANKL, P1NP, and CTX-1 concentrations were measured by enzyme-linked immunoassay. The majority of transgene effects were restricted to the 28-day-old mice. Trabecular bone volume per total volume, trabecular number, and connectivity density were greater in 28-day-old female SHP1-Tg mice when compared to WTs. SHP1-Tg female mice showed increased total and medullary areas, with no difference in cortical area and thickness. Cortical tissue mineral density was strongly genotype-dependent. Failure load, yield load, ultimate stress, and yield stress were all lower in 28-day-old SHP1-Tg females. In 28-day-old SHP1-Tg females, circulating levels of OPG and P1NP were higher and RANKL levels were lower than WT controls. Our study demonstrates a role for SHP-1 in early postnatal bone development; SHP-1 overexpression negatively impacted whole bone strength and material properties in females.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

SHP-1:

Src homology region 2 domain-containing phosphatase-1

SHP1-Tg:

SHP-1 transgenic

µCT:

Micro-computed tomography

BV/TV:

Bone volume per total volume

P1NP:

Procollagen type 1 N-terminal propeptide

CTX-1:

C-terminal telopeptide

OPG:

Osteoprotegerin

RANKL:

Receptor activator of nuclear factor kappa-B ligand

WT:

Wildtype

RANK/TRAF6:

Receptor activator nuclear factor kappa-B/TNF receptor-associated factor 6

NFĸb:

Nuclear factor kappa-B

MSC:

Mesenchymal stem cell

SIBLING:

Small integrin binding ligand, N-linked glycoprotein

MEPE:

Matrix extracellular phosphoglycoprotein

HRP:

Horseradish peroxidase

ANOVA:

Analysis of variance

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Acknowledgements

The authors express their gratitude to Dr. Tibor T. Glant for providing founders of the SHP1-Tg mouse strain. No funding was received to conduct this study.

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Authors and Affiliations

  1. Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, USA

    Adrienn Markovics, Katalin Mikecz, D. Rick Sumner & Ryan D. Ross

  2. Department of Anatomy & Cell Biology, Rush University Medical Center, Chicago, IL, USA

    Sydney Lupo, Niyati Patel, D. Rick Sumner & Ryan D. Ross

  3. Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, USA

    D. Rick Sumner

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  1. Adrienn Markovics
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Contributions

Study conception and design were provided by DRS, RDR, AM, and KM. Material preparation, data collection, and analysis were performed by AM, RDR, SL, and NP. The first draft of the manuscript was written by AM. Editing and critical review of previous versions of the manuscript were performed by RDR, DRS, and KM. All authors read and approved the final manuscript.

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Correspondence to Adrienn Markovics.

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Disclosure

Adrienn Markovics, Sydney Lupo, Niyati Patel, Katalin Mikecz, D. Rick Sumner, and Ryan D. Ross have no relevant financial or non-financial interest to disclose.

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All animal protocols were approved by the Institutional Animal Care and Use Committee (Rush University, Chicago, IL, IACUC 17–039).

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Markovics, A., Lupo, S., Patel, N. et al. SHP-1 Protein Tyrosine Phosphatase Affects Early Postnatal Bone Development in Mice. Calcif Tissue Int 112, 472–482 (2023). https://doi.org/10.1007/s00223-023-01064-5

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  • DOI: https://doi.org/10.1007/s00223-023-01064-5

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