Cell Senescence Regulating Osteoarthritis Progression: Sex-dependent Mechanisms

Osteoarthritis (OA), a leading cause of disability in the elderly (aging OA), is a complex degenerative joint disease
involving articular cartilage degradation, chronic inflammation, and bone remodeling. In addition, joint injury can
trigger post-traumatic osteoarthritis (PTOA). The prevalence and severity of knee OA are higher in women than
men during aging, although female mice are more resistant to OA progression after injury. The scientific
challenge is the incomplete understanding of the sex-specific mechanisms regulating OA progression, which
hampers the development of disease-modifying osteoarthritis drugs that can target the process. The scientific
goal of this project is to determine the molecular mechanisms underlying sex-difference in OA progression. We
discovered that retrotransposon Long Interspersed Nuclear Element-1 (LINE-1, or L1), a novel marker of cell
senescence, is closely associated with OA lesions in both human and mice. Further, L1 activation mechanism
is sex dependent. Activation of stress-inducible miR-365 stimulates L1 and OA progression in female but not in
male during aging. Furthermore, senostatics that target cell senescence inhibit OA progression by inhibiting L1,
which is repressed in chondrocytes but de-repressed in senescent MSCs in the joint. These data suggest that
senescent MSCs can be a key target for effective treatment of OA. The innovative hypothesis is that females
are more susceptible to early-onset and progression of OA during aging because stress signals stimulate L1,
which leads to MSC senescence, SASP inflammation, and joint degeneration in female. On the other hand, after
OA onset is triggered by injury, males are more susceptible to OA progression because of the higher basal levels
of L1 and IL-1β in male. If so, intervention of aging-OA progression in female and PTOA progression in male can
be achieved by repressing L1 using FDA-approved anti-viral drug nucleoside reverse transcriptase inhibitor
(NRTI). This hypothesis will be tested through three aims. First, we will define activation patterns of L1 and cell
senescence in OA cartilage lesions of male and female patients. Second, we will determine sex-specific
mechanisms regulating OA progression in aging OA and PTOA using the sex-specific OA progression mouse
models. Third, we will develop sex-specific intervention for NRTIs to inhibit OA progression. This study has high
impact because it uncovers fundamental mechanisms of OA disease disparity between men and women. It is
innovative because it represents a new and distinct direction for the field by revealing sex-specific regulation of
OA progression through addressing a previously unsuspected role of retrotransposons in these processes. It
has significant clinical and translational values. If successful, NRTIs, which are safe and readily available, can
be re-purposed for OA treatment in human. It will not only change the concepts that drive the OA research field,
but also greatly impact the clinical practice of how we treat OA patients.

Grant Number: 5R01AG080141-03
NIH Institute/Center: NIH
Principal Investigator: QIAN CHEN