Osteoarthritis (OA) is the most prevalent age-associated chronic joint disease. Although direct joint injury and excessive mechanical overloading are considered as important contributors to the development of OA, only approximately 12% of the overall prevalence of symptomatic OA is attributable to posttraumatic OA of the hip, knee, or ankle. Aging is recognized as the most important risk factor for OA, and the metabolic phenotype becomes the second most frequent subtype of OA among patients enrolled in clinical studies. Recently, it has been recognized that cellular senescence is a key driver for the progression of post-traumatic OA. However, whether and how senescent cells (SnCs) are involved in the development of non-traumatic OA remain poorly understood. In our preliminary study, we found accumulated SnCs at the joint subchondral bone marrow of both spontaneous aging OA mice and STR/Ort mice, a spontaneous OA mice associated with metabolic dysregulation. Increased SnCs were not detected in subchondral bone marrow of a post-traumatic OA mice. Therefore, subchondral bone marrow cell senescence may represent a unique feature of non-traumatic subtype of OA distinguishable from post-traumatic OA. Moreover, we identified that close to 80% of the SnCs are bone marrow Pre-osteoclast (Pre-OC). Pre-OCs isolated from old mice, relative to young mice, had increased expression of common senescence-associated secretory phenotype (SASP) factors and much higher expression of angiogenesis factor PDGF-BB, a potent angiogenesis factor. It is known that increased subchondral bone angiogenesis is a major contributor to the development of OA. Therefore, the excessive PDGF-BB secreted by subchondral bone marrow SnCs may contribute to aberrant subchondral bone angiogenesis. Our central hypothesis is that senescent Pre-OCs induce aberrant subchondral bone angiogenesis by secreting excessive PDGF-BB, leading to OA-related joint structural damage. The hypothesis will be tested by the following Specific Aims.
In Aim 1, we will trace the SnCs in synovial tissue, articular cartilage, and subchondral bone tissue of the joints by detecting the cellular senescence markers in spontaneous aging OA mice and STR/Ort mice. We will also trace the SnCs at different stages of OC lineage and verify the SASP phenotype of the cells in bone marrow of the mice.
Aim 2 will examine the necessity and sufficiency of Pre-OCs-derived PDGF-BB in age-associated subchondral bone angiogenesis and OA development.
In Aim 3, we will first define the contribution of cellular senescence to subchondral bone angiogenesis and osteogenesis by selectively eliminating the SnCs in OA mice. We will then test if blockage of Pre-OC senescence using both genetic and pharmacologic approaches attenuates OA progression.