F-spondin is a member of a family of proteins that collectively belong to a subgroup of TSR (thrombospondin) type I class molecules. We have discovered that F-spondin expression is significantly increased in osteoarthritic cartilage as well as in rodent meniscectomy models of OA. Preliminary studies indicate that F-spondin has significant effects on human chondrocyte metabolism and is also expressed in the hypertrophic regions of embryonic growth plates where it acts to regulate mineralization and endochondral bone formation. This proposal is designed to characterize the functional effects of F-spondin, which have major and previously unrecognized implications for the progression of OA. We will test two central hypotheses: 1) F-spondin modulates collagen degradation via unrecognized pathways that include activation of TGF-? and induction of MMPs and 2) F-spondin induces hypertrophic differentiation of articular chondrocytes and plays an essential role in the regulation of mineralization and endochondral bone formation.
The specific aims designed to test these hypotheses are as follows:
In SPECIFIC AIM 1 we will investigate the effects of F-spondin on the regulation of hypertrophy and mineralizing activity in human articular chondrocytes in vitro culture models. Cartilage specimens will be examined histologically to investigate the link between F-spondin and other characteristic hypertrophic/ossification markers of OA chondrocytes.
In SPECIFIC AIM 2 we will investigate the molecular mechanism(s) of F-spondin-mediated collagen degradation in OA cartilage. Explant or cell cultures will be used to a) identify MMPs induced by F- spondin and examine their role in F-spondin-mediated collagen degradation b) establish the role of TGF-? in modulation of F-spondin functions and c) compare functional activity of the full length F-spondin molecule relative to its proteolytic fragments.
In SPECIFIC AIM 3 we will identify and characterize the interacting proteins of F-spondin. a) investigate the interaction of F-spondin with the Latency-associated peptide (LAP) of the latent TGF-? complex and b) utilize yeast 2 hybrid and proteomic technologies to identify novel F-spondin binding proteins (proteases, receptors, matrix molecules) that may regulate its activity in articular cartilage.
In SPECIFIC AIM 4 we will investigate the expression and function of F-spondin in cartilage in vivo. We will investigate F-spondin expression in cartilage in vivo i) during endochondral bone development and ii) in the mouse meniscectomy model of OA. We will generate an F-spondin knockout mouse and characterize the changes in cartilage phenotype during endochondral bone development and OA disease progression. Understanding the regulation of chondrocyte functions by F-spondin could lead to novel strategies for cartilage repair and disease modifying treatments for osteoarthritis.
Osteoarthritis affects more than 20% of the population over age 60 and for millions of people is a significant cause of disability. This research proposal will focus on a protein, F-spondin, never before described in cartilage, which regulates processes that are important in joint deterioration in osteoarthritis. The proposed experiments are designed to identify previously unrecognized pathological events that lead to new treatments for osteoarthritis, which prevent the progression of disease, reduce the likelihood of disability and improve the public health.
|O'Connell, Grace D; Tan, Andrea R; Cui, Victoria et al. (2017) Human chondrocyte migration behaviour to guide the development of engineered cartilage. J Tissue Eng Regen Med 11:877-886|
|Katsara, Olga; Attur, Mukundan; Ruoff, Rachel et al. (2017) Increased Activity of the Chondrocyte Translational Apparatus Accompanies Osteoarthritic Changes in Human and Rodent Knee Cartilage. Arthritis Rheumatol 69:586-597|
|Jain, Manish; Attur, Mukundan; Furer, Vika et al. (2015) Increased plasma IL-17F levels in rheumatoid arthritis patients are responsive to methotrexate, anti-TNF, and T cell costimulatory modulation. Inflammation 38:180-6|
|Attur, Mukundan; Yang, Qing; Shimada, Kohei et al. (2015) Elevated expression of periostin in human osteoarthritic cartilage and its potential role in matrix degradation via matrix metalloproteinase-13. FASEB J 29:4107-21|
|Moon, Paxton M; Penuela, Silvia; Barr, Kevin et al. (2015) Deletion of Panx3 Prevents the Development of Surgically Induced Osteoarthritis. J Mol Med (Berl) 93:845-56|
|Palmer, Glyn D; Attur, Mukundan G; Yang, Qing et al. (2014) F-spondin deficient mice have a high bone mass phenotype. PLoS One 9:e98388|
|Scher, Jose U; Ubeda, Carles; Equinda, Michele et al. (2012) Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum 64:3083-94|
|Attur, Mukundan; Ben-Artzi, Ami; Yang, Qing et al. (2012) Perturbation of nuclear lamin A causes cell death in chondrocytes. Arthritis Rheum 64:1940-9|
|Wang, Ligong; Salibi, Nouha; Chang, Gregory et al. (2012) Assessment of subchondral bone marrow lipids in healthy controls and mild osteoarthritis patients at 3T. NMR Biomed 25:545-55|
|Todorovic, Vesna; Rifkin, Daniel B (2012) LTBPs, more than just an escort service. J Cell Biochem 113:410-8|
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