# Pericellular Proteolysis and the Regulation of Bone/Tendon Stem Cell Fate

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $434,981

## Abstract

ABSTRACT
Bone as well as tendons each contain stem cell populations embedded in type I collagen-rich tissues. Bone
marrow and endosteal-derived stem cells generate bone via endochondral ossification while periosteal stem
cells form bone via the intramembranous route. In turn, tendon stem cells give rise to tenocytes that populate
the mature tissues. Recent studies have identified the cysteine proteinase, cathepsin K (CTSK), as a unique
marker of periosteal stem cells, a finding we have confirmed, but that also led to our identification of a heretofore
uncharacterized second stem population associated with tendons. In bone marrow-derived MSCs, we have
previously identified a novel requirement for the membrane-anchored metalloproteinase, MT1-MMP, in
regulating a mechanosensitive, YAP/TAZ-dependent pathway that controls stem cell lineage commitment via
the proteolytic remodeling of the pericellular collagen matrix. By contrast, the relative roles of MT1-MMP and
CTSK in periosteal or tendon/ligament stem cells are unknown. Using a Ctsk-Cre transgenic line to target
periosteal stem cells, we find that Mt1-mmp targeting alone elicits a profound osteopenic state in vivo that not
only operates independently of Ctsk, but also redirects the stem cells to an aberrant hyperproliferative,
chondrogenic state. Further, and unexpectedly, Ctsk-Cre–dependent targeting of MT1-MMP - but not Ctsk,
disrupts tendon/ structure by altering a previously undescribed paratenon stem cell-tendon trafficking route. In
vivo, MT1-MMP-null tendon stem cells commit to a hyperproliferative, chondrogenic phenotype similar to that
observed following tendon/ligament trauma. Based on these new data, we propose that MT1-MMP controls
each of these stem cell populations by regulating a mechanotransduction pathway that not only controls
YAP/TAZ-linked co-transcriptional programs, but also canonical TFGβ signaling pathways via the proteolytic
shedding of the accessory TGFβ receptor, TGFβRIII. Together, these findings outline a new model of MSC
function wherein MT1-MMP-dependent collagenolysis and receptor shedding together play a required role in
periosteal tissues and tendons. As such, we propose 3 aims; i) characterize the role of MT1-MMP in regulating
periosteal stem cell differentiation and function in vitro and in vivo, ii) define a novel role for Ctsk+ tendon stem
cells in controlling tendon function and its regulation by MT1-MMP and iii) delineate the impact of MT1-MMP on
periosteal/paratenon stem cell YAP/TAZ mechanotransduction and TGFβ/TGFβRIII- dependent differentiation
programs. Together, these aims should cast new light on a family of specialized stem cells that require MT1-
MMP-dependent proteolysis to not only regulate intramembranous bone formation, but also tendon
structure/function as well.

## Key facts

- **NIH application ID:** 10371563
- **Project number:** 1R01AR078783-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** STEPHEN J WEISS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $434,981
- **Award type:** 1
- **Project period:** 2022-08-05 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371563

## Citation

> US National Institutes of Health, RePORTER application 10371563, Pericellular Proteolysis and the Regulation of Bone/Tendon Stem Cell Fate (1R01AR078783-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10371563. Licensed CC0.

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