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Principal Investigator: Lin Han
Organization: DREXEL UNIVERSITY
Fiscal Year: 2024
Award: $326,990
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
PROJECT SUMMARY
The development of novel cartilage regeneration and osteoarthritis (OA) treatments is limited by our
incomplete understanding of how certain molecular activities in cartilage extracellular matrix (ECM) are linked
to its matrix assembly and biomechanical functions. This project will study the activities of decorin, a small
leucine rich proteoglycan (SLRP), which appears to be critical for the assembly and stability of the aggrecan
network, a major constituent of cartilage ECM. The overall objective is to determine the roles of decorin in
regulating the assembly of the aggrecan network in healthy and degenerative cartilage. Our central hypothesis
is that decorin acts as a “physical linker” to regulate the assembly of the aggrecan network in cartilage ECM,
and this role enables the establishment of the normal biomechanical function of cartilage during joint
development, and delays cartilage degeneration in OA by increasing the retention of fragmented aggrecan.
We will elucidate the roles of decorin in normal cartilage ECM assembly (Aim 1) and in OA-associated
cartilage degradation (Aim 2), respectively. In Aim 1, we will first determine whether decorin is essential for the
proper biomechanical function of normal cartilage during post-natal growth. Next, we will determine whether
decorin increases the retention of aggrecan in the forming neo-matrix of chondrocytes under dynamic loading,
and if decorin also regulates chondrocyte anabolic response to growth factors. In Aim 2, we will first determine
whether decorin slows down cartilage degradation and OA progression using two murine OA models, including
naturally occurring OA in aged mice and injury-induced post-traumatic OA in the destabilization of the medial
meniscus (DMM) model. Next, we will determine if decorin increases the retention of aggrecan fragments in
degenerative cartilage, and if decorin also directly impacts chondrocyte catabolism in response to inflammatory
factors. A number of innovative approaches will be utilized. Using cartilage-specific decorin inducible knockout
mice, we will delineate decorin activities during normal cartilage homeostasis and those during the progression
of OA. Applying atomic force microscopy (AFM)-nanomechanical tests, we will quantify the mechanical
changes of cartilage as a result of decorin deficiency. By combining these approaches, we will elucidate the
roles of decorin in regulating the structure and function of normal cartilage, and the degradation of cartilage
during OA onset and progression. Successful completion of this study will establish a new structure-mechanics
principle of decorin-mediated aggrecan network assembly in the cartilage ECM. This will direct our future
studies to improve cartilage regeneration and to slow down OA progression by modulating the activity and
availability of native decorin, as well as the design and delivery of decorin-biomimetic synthetic molecules.
Terms: <Acceleration><Adhesions><Atomic Force Microscopy><Autoregulation><Beta Proprotein Interleukin 1><Bioavailability><Biological><Biological Availability><Biological Mimetics><Biomechanics><Biomimetics><Bone-Derived Transforming Growth Factor><Cartilage><Cartilage Matrix><Cartilaginous Tissue><Catabolism><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Extracellular Matrix><Cells><Chondrocytes><Collagen><Data><Degenerative Arthritis><Degenerative polyarthritis><Development><Disease><Disorder><ECM><Event><Experimental Designs><Extracellular Matrix><Force Microscopy><Future><Generalized Growth><Growth><Growth Agents><Growth Factor><Growth Substances><Health><Homeostasis><IGF-1><IGF-I><IGF-I-SmC><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Impairment><In Vitro><Inflammatory><Injury><Insulin-Like Growth Factor 1><Insulin-Like Growth Factor I><Insulin-Like Somatomedin Peptide I><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intracellular Communication and Signaling><Joints><KO mice><Knock-out Mice><Knockout Mice><Leucine><Link><Load Bearing><Mechanics><Medial Menisci><Medial meniscus structure><Mediating><Meniscus Medialis><Mice><Mice Mammals><Milk Growth Factor><Modeling><Molecular><Murine><Mus><Null Mouse><Operative Procedures><Operative Surgical Procedures><Osteoarthritis><Osteoarthrosis><Pathway interactions><Physiologic><Physiologic Availability><Physiological><Physiological Homeostasis><Platelet Transforming Growth Factor><Play><Preinterleukin 1 Beta><Production><Property><Proteins Growth Factors><Proteoglycan><Receptor Protein><Role><Scanning Force Microscopy><Signal Transduction><Signal Transduction Systems><Signaling><Somatomedin C><Spectroscopy><Spectrum Analyses><Spectrum Analysis><Structure><Surgical><Surgical Interventions><Surgical Procedure><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Time><Tissue Growth><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Traumatic Arthritis><Traumatic Arthropathy><Weight Bearing><Weight-Bearing state><absorption><aged mice><aged mouse><aggrecan><biologic><biological signal transduction><biomechanical><cartilage degeneration><cartilage degradation><cartilage regeneration><decorin><degenerative joint disease><design><designing><developmental><elderly mice><femur head><hypertrophic arthritis><improved><in vivo><injuries><innovate><innovation><innovative><mechanic><mechanical><mechanical properties><nano mechanics><nanomechanics><natural aging><normal aging><normative aging><novel><old mice><ontogeny><osteoarthritic><pathway><post-traumatic osteoarthritis><postnatal><receptor><receptor binding><receptor bound><response><social role><surgery>