Mouse Models for SLRP Roles in Tendon Aging and Impaired Healing in Aging Tendons

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 DESCRIPTION (provided by applicant): Tendon injuries are a common problem exacerbated in the aging population. Significant pain and disability are associated with these injuries resultig in decreased quality of life, loss of work and independence. Interactions involving small leucine-rich proteoglycans (SLRPs) and other matrix molecules are central to the regulation of the hierarchical assembly of tendon, as well as in the establishment or re-establishment of tendon mechanical function. The class I SLRPs, decorin and biglycan, exhibit alterations in expression during growth, aging and in the injury response. The absence of decorin ameliorates the mechanical and fibril parameter changes associated with aging and is detrimental to the tendon injury response. These data suggest critical regulatory roles for SLRPs in tendon. Unfortunately, progress in this area has been limited by the model systems available. Use of conventional knockout mice does not allow control of temporal or spatial specificity and secondary and compensatory effects cannot be controlled. To address this, we developed inducible-null mouse models to isolate age and injury specific effects while avoiding confounding issues. The overall goal of this proposal is to delineate the coordinated mechanisms whereby alterations in decorin and biglycan expression influence the detrimental effects seen during the aging, as well as in injury and repair processes. During tendon aging, the interactions involving SLRPs that result in an impaired injury response will be defined. Our general hypothesis is that tendon aging and the impaired age-associated response to tendon injuries are the result of similar SLRP-mediated mechanisms. Specifically, sequential changes in the differential expression of biglycan and decorin provide coordinate regulatory interactions required for re-establishment of tendon structure and function. These patterns are disrupted with aging resulting in altered structure, function and repair ability. The study aims are: Aim 1: Define mechanisms whereby SLRPs influence tendon aging. Aim 2: Define the mechanism whereby aging alters the regulatory role(s) of SLRPs in the tendon injury response. Aim 3: Determine the differential effect(s) of the addition of SLRPs in the tendon injury response with aging. We will utilize our novel inducible mouse models and exploit their temporal specificity to systematically define the roles of decorin and biglycan in tendon aging and in the associated altered injury response. This will be coupled with systemic administration of SLRPs to generate four distinct compositions for analyses of the mechanistic roles. Our flexor tendon injury model coupled with sophisticated and innovative measures of mechanical and organizational properties, together with compositional profiles will be used to derive a mechanistic understanding of these responses. Further, these analyses will provide a fundamental understanding of the regulatory interactions of decorin and bigylcan in aging and in the injury response. Finally, this information will provide a framework for further investigation into the contrasting and potentially synergistic roles of these SLRPs that will aid i the design of improved treatments for age associated tendon injuries.