# A novel regulating pathway in osteoclastogenesis and arthritic bone resorption

> **NIH NIH R01** · HOSPITAL FOR SPECIAL SURGERY · 2020 · $389,706

## Abstract

Osteoclasts are large myeloid-derived multinucleated cells primarily responsible for bone
resorption. Dysregulation of osteoclast differentiation can result in net bone resorption and is key to the
pathophysiology of rheumatoid arthritis, osteoporosis, and lytic bone metastasis. Thus, understanding the
mechanism of osteoclast differentiation is of great therapeutic importance for nearly all forms of metabolic
bone disease. Our long-term goals are 1) to elucidate a role of the newly described regulatory pathway in
osteoclastogenesis and arthritic bone resorption and 2) to develop an effective and specific way to treat
bone loss in RA. c-FMS, a receptor for M-CSF/ IL-34, transduces essential signals for the differentiation of
osteoclasts and macrophages. Aberrant expression of c-FMS (or M-CSF) has been linked to exacerbation
of diseases such as inflammatory arthritis and cancers. We have identified a novel regulatory pathway of
c-FMS initiated by TACE (TNF-α converting enzyme). This pathway involves the coordinated, sequential
cleavage of c-FMS by TACE, γ-secretase, and calpain, which results in the generation of intracellular
domain cleavage fragments (referred to as FICD). Myeloid-specific TACE-deficient mice have high bone
mass with decreased osteoclast numbers and ameliorate bone destruction in TNF-α induced arthritis in
TNF transgenic (tg) mice. We found that FICD generation is critical for osteoclastogenesis, as enforced
expression of FICD rescues the impaired osteoclastogenesis seen in TACE deficient cells. Thus, in
addition to the well known role of c-FMS to activate conventional M-CSF signaling pathways as a surface
receptor, c-FMS is also processed into the FICD that traffics into the nucleus, where it functions as a
positive regulator of osteoclastogenesis. The existing paradigm is that shedding of c-FMS from the cell
surface is a negative event related to loss of a signaling receptor. However, our study led us to discover
that TACE-mediated shedding of c-FMS provides a positive signal for osteoclastogenesis. Here, we seek
to build upon our novel findings to unravel the mechanisms by which the TACE/FICD axis regulates bone
resorption, with a specific focus on inflammatory arthritis. Thus, we hypothesize that :1) TACE deficiency-
mediated attenuation of arthritic bone resorption is, in part, due to lack of FICD, 2) Inhibition of the
TACE/FICD axis ameliorates arthritic bone resorption, and 3) FICD targets the transcriptomic program in
osteoclastic bone resorption. Our specific aims are 1) to investigate the underlying mechanisms behind
how the TACE/FICD axis regulates pathological bone resorption in TNF-tg mice and 2) to elucidate the
mechanism by which the TACE/FICD axis regulates osteoclastogenesis by identifying the direct
pathways/targets of FICD. We anticipate that a better understanding of the diverse roles of this TACE/c-
FMS/FICD pathway will advance our understanding of fundamental osteoclast biology, and targeting the
TACE/FICD ...

## Key facts

- **NIH application ID:** 9847950
- **Project number:** 5R01AR073156-03
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** Kyung-Hyun Park-Min
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,706
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847950

## Citation

> US National Institutes of Health, RePORTER application 9847950, A novel regulating pathway in osteoclastogenesis and arthritic bone resorption (5R01AR073156-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9847950. Licensed CC0.

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