Abstract
A major goal of regenerative medicine is to stimulate tissue regeneration after traumatic injury. We previously discovered that treating digit amputation wounds with BMP2 in neonatal mice stimulates endochondral ossification to regenerate the stump bone. Here we show that treating the amputation wound with BMP9 stimulates regeneration of a synovial joint that forms an articulation with the stump bone. Regenerated structures include a skeletal element lined with articular cartilage and a synovial cavity, and we demonstrate that this response requires the Prg4 gene. Combining BMP2 and BMP9 treatments in sequence stimulates the regeneration of bone and joint. These studies provide evidence that treatment of growth factors can be used to engineer a regeneration response from a non-regenerating amputation wound.
Highlights
A major goal of regenerative medicine is to stimulate tissue regeneration after traumatic injury
To investigate joint morphogenesis and whether mammalian joints can regenerate, we have focused on a BMP family member, BMP9, which is expressed by interzone cells of the forming synovial cavity and lacks a Noggin binding domain[12]
Since joint formation fails in mice lacking the BMP antagonist Noggin, and BMP9 is refractory to Noggin inhibition, its expression during joint morphogenesis raised the possibility that BMP9 can act as a regenerative agent to stimulate joint regeneration
Summary
A major goal of regenerative medicine is to stimulate tissue regeneration after traumatic injury. Regenerated structures include a skeletal element lined with articular cartilage and a synovial cavity, and we demonstrate that this response requires the Prg[4] gene. One strategy to enhance mammalian regenerative responses is to use developmental agents to re-initiate morphogenesis at non-regenerative amputation wounds[3], and this strategy has been used successfully to stimulate bone regeneration with targeted treatment of bone morphogenetic protein 2 (BMP2) or BMP74–8. Transient treatment of the amputation wound with BMP2 induces formation of an endochondral ossification center that organizes the regeneration response of the amputated stump bone[4,5]. We demonstrate that treating non-regenerative digit amputation wounds with BMP9 stimulates the regeneration of joint structures. The regenerated joint includes a synovial cavity and a skeletal element lined with articular cartilage that articulates with the amputated bone stump. Our findings demonstrate that growth factor treatment can be used to overcome mammalian regenerative defects, and provides further evidence that regenerative failure in mammals is associated with a defective wound environment
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