Osteoarthritis (OA) is the most common degenerative joint disorders and the leading cause of physical disability.There is no effective disease modifying treatment for OA except the joint replacement surgery. We have revealedthat aberrant subchondral bone remodeling leads to degeneration of joint articular cartilage. Elevated osteoclastresorption in the OA subchondral bone leads to excessive TGFβ1 that uncouples bone resorption and formationand resulted in deterioration of subchondral bone. Restoring the structural integrity of subchondral bone byinhibiting TGFβ activity in subchondral bone can prevent OA progression and cartilage degeneration.Pain is the most prominent symptom of OA that urged people to seek for medical care. Our preliminary studysuggests that osteoclasts derived factor induces axonal extrusion and innervations in the subchondral bone andsubstantially contribute OA pain. Zoledronic acid, a bisphosphonate that inhibits osteoclasts activity, has beenreported effective in reducing knee pain and the BMLs size.Suppressing of TGFβ signaling pathway with type I TGFβ receptor inhibitor has been demonstrated to rescuesubchondral bone pathology and attenuate cartilage degeneration. However, TGFβs are multifunctionalcytokines that are involved in a range of biological processes. Systemic inhibition of TGFβ signaling may lead toa failure in the maintenance of tissue homeostasis of other organs, particularly articular cartilage where TGFβsevers as a major anabolic factor. Thus, it is of great importance to develop a novel strategy that can retain orperhaps even increase the efficacy of the TGFβ inhibitor while improving its safety in the therapeutic applications.We have synthesized a novel drug that conjugates alendronate (ALN), a bisphosphonate drug, with LY 2109761(LY), a selective TβRI and TβRII kinase inhibitor, through a metabolically cleavable linker. Utilizing the high affinityof ALN, we achieve bone targeted delivery and sustained bone release of TβR inhibitor. Moreover, we anticipatethat this conjugate has superior effect in alleviating OA pain as ALN has also been known to relieve bone pain.In this application, we propose to investigate the effects of the conjugate in preventing the development ofosteoarthritic pathologies as well as alleviating joint pain. We will also optimize the treatment dosage, frequencyand evaluate the toxicity of the conjugate in OA animal model. The results are expected to provide a strongtechnological and theoretical foundation for future clinical trials.
Public Health Relevance Statement: Osteoarthritis is a common joint degenerative disease that causes a huge economic burden. Currently there is
no effective disease-modifying treatment for OA. Osteoclastic bone resorption induces OA pain and excessive
TGFβ activation, which consequently contribute to subchondral bone deformity and cartilage degeneration. We
are working to develop a patent-protected novel conjugate drug by combination of the TβRI inhibitor with a
bisphosphonate drug, which inhibits osteoclast activity and has a high affinity to bone. The success of the
conjugate may highlight an unmet need for effective therapeutic approaches with minimized side-effects and
chemical toxicity for OA patient.
Project Terms: | <2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonic acid> | | |
