Osteoarthritis (OA) is the most prevalent joint disease and a major cause of disability. Aging is the major risk factor for OA which begins with disruption of the cartilage superficial zone (SZ). Molecular mechanisms that determine the unique phenotype of cells in the SZ are unknown and information on causes of the initial cartilage surface defects is limited. Our preliminary studies show that the chromatin protein HMGB2 is exclusively expressed in the SZ of articular cartilage. We examined Hmgb2-/- mice and found more severe OA as compared to wild-type (WT) mice. In human and WT mouse joints there is an aging-related reduction and loss of HMGB2 expression followed by degenerative changes in the cartilage surface. These findings support our hypothesis that HMGB2 is involved in cartilage homeostasis and aging-related loss of HMGB2 expression is a mechanism involved in disruption of the SZ and early OA. The goals of the proposed study are to investigate how aging-related reduction of HMGB2 affects cartilage integrity and address molecular and cellular mechanisms of HMGB2.
Aim 1. HMGB2 deficiency in murine and human joints. We will analyze onset, evolution and patterns of cartilage degeneration in Hmgb2-/- mice and examine mechanisms of OA pathogenesis in Hmgb2-/- mice involved in spontaneous and surgically induced OA. These findings will be confirmed with human articular cartilage.
Aim 2. HMGB2 in articular chondrocytes. We will characterize phenotype and differentiation status of HMGB2-expressing cells. Studies will be performed on regulation of HMGB2 expression in cultured chondrocytes and we will determine the role of HMGB2 in regulating survival and biosynthetic responses in SZ chondrocytes.
Aim 3. Mechanisms of HMGB2 regulation of cell function: interactions with Lef-1 and ss-catenin. We will map essential motifs involved in the physical interaction of HMGB2 and Lef-1. We will address function of ss- catenin interaction with HMGB2 and in expression of Lef-1 dependent genes, SZP and survival genes. Superficial zone-specific deletion of ss-catenin will be obtained by conditional knock out of ss-catenin by intraarticular injection of adenovirus expressing Cre recombinase. The proposed studies have the potential to generate new insight into molecular mechanisms that control the unique differentiation status of SZ chondrocytes. This information will not only be relevant to OA but also to cartilage tissue engineering. The proposed studies will provide insights into mechanisms of early degenerative changes in the articular cartilage and may permit development of preventive and therapeutic strategies for OA.

Public Health Relevance

Osteoarthritis represents the most prevalent joint disease and is a major cause of disability. Disease-modifying therapies are not available and this is in part related to an incomplete understanding of pathogenetic mechanisms. Specifically, osteoarthritic lesions begin at the articular cartilage surface which is important in biomechanical function and joint lubrication and then progress to larger lesions with complete loss of cartilage. Information on the causes of the initial cartilage surface defects is very limited. Our preliminary studies show that the chromatin protein HMGB2 is exclusively expressed in the superficial zone of articular cartilage from human and murine joints. With advancing age there is a reduction and loss of HMGB2 expression that is followed by loss of cartilage cells and the onset of degenerative changes in the cartilage surface. These observations suggest that HMGB2 is a critical factor for maintaining the integrity of the cartilage surface and that its aging-related loss is a central pathogenetic mechanism in osteoarthritis. The proposed research has the potential to identify new avenues for the prevention and treatment of osteoarthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056026-04
Application #
8277985
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$406,082
Indirect Cost
$192,242
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Shapiro, Irving M; Layfield, Robert; Lotz, Martin et al. (2014) Boning up on autophagy: the role of autophagy in skeletal biology. Autophagy 10:7-19
Levy, Yadin D; Hasegawa, Akihiko; Patil, Shantanu et al. (2013) Histopathological changes in the human posterior cruciate ligament during aging and osteoarthritis: correlations with anterior cruciate ligament and cartilage changes. Ann Rheum Dis 72:271-7
Hasegawa, Akihiko; Nakahara, Hiroyuki; Kinoshita, Mitsuo et al. (2013) Cellular and extracellular matrix changes in anterior cruciate ligaments during human knee aging and osteoarthritis. Arthritis Res Ther 15:R29
Grogan, Shawn P; Duffy, Stuart F; Pauli, Chantal et al. (2013) Zone-specific gene expression patterns in articular cartilage. Arthritis Rheum 65:418-28
Lotz, M (2012) Osteoarthritis year 2011 in review: biology. Osteoarthritis Cartilage 20:192-6
Carames, Beatriz; Taniguchi, Noboru; Seino, Daisuke et al. (2012) Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection. Arthritis Rheum 64:1182-92
Monemdjou, Roxana; Vasheghani, Faezeh; Fahmi, Hassan et al. (2012) Association of cartilage-specific deletion of peroxisome proliferator-activated receptor ? with abnormal endochondral ossification and impaired cartilage growth and development in a murine model. Arthritis Rheum 64:1551-61
Carames, Beatriz; Hasegawa, Akihiko; Taniguchi, Noboru et al. (2012) Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis 71:575-81
Lotz, Martin; Loeser, Richard F (2012) Effects of aging on articular cartilage homeostasis. Bone 51:241-8
Lotz, Martin; Carames, Beatriz (2012) Autophagy: a new therapeutic target in cartilage injury and osteoarthritis. J Am Acad Orthop Surg 20:261-2

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