Xu Cao, Ph.D. featuring Matt Greenblatt, M.D, Ph.D.

In this episode of JBMR at 40, host Matt Greenblatt sits down with Dr. Xu Cao of Johns Hopkins to explore a career defined by discovery across the bone field. Dr. Cao reflects on his pioneering work uncovering how osteoclasts and osteoblasts are coupled through TGF-β signaling—findings that reshaped our understanding of bone remodeling and seeded new insights into angiogenesis, pain, and osteoarthritis.

The conversation traces how seemingly distinct research areas converge on a central theme of coupling, extending from cellular biology to brain–bone communication. Dr. Cao also shares lessons from his time as a JBMR editor, advocating for a more multidisciplinary future that integrates biomechanics, neuroscience, and clinical perspectives.

Closing with candid advice for early-career scientists, he emphasizes hypothesis-driven thinking, resilience in lean funding climates, and the importance of curiosity in tackling the field’s biggest unanswered questions.

Transcript

SPEAKER_01 0:03

So hello everyone. I'm Matt Greenblatt here at Wild Cornell Medicine in New York City. And today I'm acting as an associate editor of the Journal of Bone and Mineral Research and really excited to have the chance to interview Dr. Shu Zhao, who is the Lee Riley Professor in the Department of Orthopedic Surgery at Johns Hopkins and also the director of the Musculoskeletal Center for Musculoskeletal Research there. So Dr. Tao, really excited to have the chance to chat with you today. I feel nice to be able to do that. So in getting ready for this conversation and thinking about your work, something that really struck me is that you've made contributions in a lot of different areas within the bone field, including mechanisms coupling bone absorption to bone formation, skeletal angiogenesis, and now work on osteoarthritis and how that links to bone metabolism. So could you just tell us the story of you know, out of all those areas, which one do you think is the most impactful and kind of the story of how that work came to be?

SPEAKER_00 1:14

Yes, Matt, uh this is uh uh uh uh very good question. Uh so uh in my research, uh I always think uh uh you know which one we did uh had an impactful. So actually, the most uh important work, I think uh what we did is uh coupling mechanism of osteoclass osteoplast. So we did this about uh 20 years ago. Uh uh we spent uh finally find the TGA beta eliberated from osteoclass resorption, uh recruit a stem cell, make uh resorption and coupling with uh uh bone formation. Actually, uh at that time, this is uh a critical question in the bone field, I personally think. Uh we spend uh uh five years for this project, and uh uh uh then we spent another three years to publish it. So uh people uh uh at the beginning hard to uh believe TJ beta induced migration of stem cell. But uh uh uh 80 years better, uh eventually uh uh we published, and uh uh that work uh produced a very fundamental uh uh mechanism for the bone remodeling and disease as well. So from there uh we found uh actually it is also classed during remodeling. So that secret PDJBB, uh induce angiogenesis H-type vessel. Okay. In addition, actually uh it also uh uh secrete uh uh release IGF1 for bone formation and quality. And uh recently we found uh it is still also classed secret nitrogen to induce in nerve innervation. Uh that one actually causes disease for oil pain, for uh spine pain. And uh uh uh more importantly, uh actually we found uh uh when uncoupled bone remodeling, it generates uh porosity structure uh in subchondial bone and the end plate. Uh uh amazingly, we found actually our brain monitors the bone remodeling every minute. Okay, so it is the uh uncoupled uh remodeling changes uh uh concentration of PG2. That is the interoceptive molecule perceived by the brain. So uh so the most impactful work uh I think is uh coupling.

SPEAKER_01 4:00

Yeah, so I I guess what I hear you saying is that all these different areas that might seem to be distinct are really linked by this common thread of study of coupling and maybe early osteoclass activity.

SPEAKER_00 4:12

Exactly. Uh I found uh this logically linked. As long as your experimental results are accurate, it will lead to your other area for discovery.

SPEAKER_01 4:25

And from my perspective, you know, that really is a the the approach in that key work on TGF data uh was was very new for the field at the time, although now there have been more similar work subsequently, including in your own work. So tell us a little bit about how you started that story. Why did you pick that direction given the newness of the approach and the concepts introduced there? Was this something that just emerged from prior work, or was this something that you said, I want to go after this, this is this is where I want to make my mark?

SPEAKER_00 5:00

No. Uh actually, uh uh you know, I trained in chemistry. So the first uh uh few years in uh as a faculty, I did a lot of signaling paper publisher, but I found uh uh they are not uh solved any important uh problems uh in the bone field. So uh I spent time to think what is the most important question at that time. I found uh uh bone remodeling, coupling osteoblast osteoplast. Uh I I was not uh uh aimed to study TJ beta. So we did a bone resorption, see what factor actually released. So we did all of them. So the data tells us that it is TJ beta is the highest one, and the induced migration. That's how we come up for it is the uh accurate data lead to TJ beta.

SPEAKER_01 5:59

So changing gears just a little bit, uh, I know that you're previously a senior associate editor at JBMR. So because we're here uh in a JBMR um interview, uh sponsored interview, could you talk a little bit about what did you learn? What was your takeaways from being an editor? Um, what perspective did that give you on the field?

SPEAKER_00 6:21

Okay, uh first uh I would like to congratulate uh JBRMR uh for 40 years anniversary. And JBRMR uh uh uh made a fundamental contribution uh in the field of Boone. And uh I benefit a lot. I read a uh at an early stage, I read a most important paper always from JBMR. I personally published my first JBMR paper in 1992. And uh since then I regularly publish there, I published many papers uh in JBMR. But uh uh I at uh uh one time I served as a senior editor. Uh uh, so uh uh I learned more about uh GBMR. Uh I really appreciate uh uh everybody published paper there, and appreciate uh the year's editor-in-chief and uh associate editor made the uh effort uh for the journal for SBMR for the society. So, in my own experience, uh uh uh uh what I feel uh GBMR made a good uh contribution in terms of uh conventional uh bone remodeling and metabolism and uh related uh conventional endocrine uh uh uh uh modulation of bone. So we publish a lot of paper. When it comes to this stage, further uh study probably uh use the knowledge we publish to conquer other major diseases. Okay. So in doing so, uh it appears uh to me uh just the single angle to attack the uh issue probably not sufficient. It probably involved uh uh uh multidisciplinary. For example, if you have OA, uh the mechanics probably the top cause the problem for osteoard uh arthritis, and you know, uh post-traumatic osteoarthritis. So it so that causes pain. So that we will know. So uh the osteo class boring modeling change, that's another thing. So if you can uh uh solve the uh uh uh uh comprehensive the problem, probably need uh other discipline, other areas of efforts. So I feel uh for the long-term future uh GBMR uh should uh go along with the development uh of the study multidisciplinary. So sometimes uh a breakthrough can be from a stem cell uh for the bone field. Therefore, uh if it's a stem cell study, it's important. I think uh we should be inclusive. Uh it could be a pain. So uh uh that is not a conventional, uh we still need uh uh consider. Uh biomechanics uh is so important uh for the bone. Sometimes it's a key discovery is from uh a point of view of uh biomechanics. That paper looks like uh a distal from uh conventional uh bone metabolism. However, if that's an innovative or critical novelty for the field and uh still should be considered published in GBMR. So I uh uh uh that's just uh my uh uh personal uh view uh of my personal experience. Hopefully, uh GBMR will do better uh for another uh uh decade, uh another 40 years, uh coming to serve for everybody.

SPEAKER_01 10:13

Yeah, and how do you think what do you think is the most effective way to uh achieve kind of the goals that you outlined? So you're I hear you talking about bringing biomechanics in at a deeper level, bringing in uh neural bone interactions at a deeper level. How do we effectively nucleate that as as as really core areas within the field?

SPEAKER_00 10:44

Okay. Uh I I think uh uh uh because uh uh our field has a traditional group of uh uh professors and scientists read the journal constantly. So however, uh uh uh we know little about the other field. Actually, uh what I know uh in neuroscience, in the pain field, they uh spend uh a lot of effort uh understanding the skeletal pain as well. Okay. So uh we should be able to invite uh uh from publication should invite them uh write uh reviews for our journal at the beginning. And uh uh so publish some of the paper and gradually so we can identify uh the critical field by inviting reviews in that field, so uh that can uh you know, within the uh editorial and uh senior members in uh SPML can discuss so uh uh what are the papers uh and uh uh studies and reviews uh should be included at the beginning. I think that will take time gradually. Uh people eventually will come to a consensus.

SPEAKER_01 12:09

That makes good sense. I I can say sometimes the challenge there is convincing outside experts that bone is important enough or that bone is on their radar that they should invest time in connecting with the bone field.

SPEAKER_00 12:25

I see. Uh it is. Uh um so uh uh for myself, for example, uh about 10 years I realize uh uh the pain because I'm in orthopedics, I talk to surgeons. Uh I feel embarrassed. Uh we published a lot of papers. Uh they told me, oh, your paper looks good. Does not solve problems. So uh I I try to talk to them. Uh, what is the problem? So uh the major uh uh uh skeletal joint disease is uh spine degeneration and uh OA. So uh the mechanism is unclear. So the most effective way is surgery. Uh I was very surprised. So the patient when came, uh they they they tell uh you uh it's pain. Some some of them uh MI tells uh they're fine, but they're pain. They come to uh the doctor want to change the joint. So pain is an important question. I learned from uh the surgeons, clinicians. So then I talked to the top notch uh pain scientists, the neuroscientist at GGO. So we collaborate uh uh about 10 years ago, we published, I learned a lot from them. We published a paper together. You know, 10 years later, all my collaborators are working on OA pain and spine pain. Same as me. So I learned from them, they find uh uh, you know, when as a neuroscientist uh they study pain, uh they don't know the origin of the pain source. They don't know bone disease. Body can do anything above spine cord and above. So the pain mechanism above spine cord, they're the same. So you you kill the pain, you did not modify the disease, make it worse. And uh opioid treatment uh feel comfortable, you addicted uh uh cause a society problem. So NH wasn't interested to find uh those types of things, but they want to modify the disease of the pain. So uh almost all of our initial collaborators, I try to learn from them. Now they uh everybody writes uh pain grant uh for OE or spine. Uh they uh drive all the way to my lab to learn the animal model. So uh uh I I think they are interested. Okay. Uh I think uh for GBMR to outreach them, and uh I think they are very happy to write uh reviews uh for us. And uh they uh they needed to learn, uh we need to learn uh from them, and uh uh the interaction is uh already there.

SPEAKER_01 15:15

Yeah. So so I guess in other words, you kind of led the way yourself in forging these collaborations with people that were traditionally outside the field, uh, and and kind of offer them the bone as an opportunity to demonstrate the importance of the mechanisms that maybe they were studying in other contexts.

SPEAKER_00 15:35

Yes, uh I uh because I was working on also class that's uh at the beginning is learning uh with uh uh uh uh Steve Tedbaum. Well, sadly, uh uh I just saw uh uh say uh uh Dr. Steve uh Tetbaum passed away last month is a great loss. But anyway, I learned uh also class uh uh uh from him. I found that the bone is uh fascinating. Okay, uh it's uh uh uh uh uh chemopoids is a stem cell, uh nerve, and a joint uh is controlled by the brain. So uh when I interact uh with my neuroscience colleagues, they find uh same as what uh I feel is fascinating. Uh it's uh uh uh they're interested, I think. Uh so uh uh that's uh uh we are working on uh a very interesting uh uh uh field. Okay.

SPEAKER_01 16:34

So maybe changing gears a little bit. Uh I know it's no secret that now is a very difficult time for research, probably especially for early career researchers. And with your perspective, what advice would you offer for early career researchers that are really facing some pretty substantial challenges right now?

SPEAKER_00 16:55

Yeah. Uh uh I I work on the lab over 30 years, uh, experience a lot of up and down times. Uh so uh uh we managed uh uh uh go through, but uh none of them as uh uh compared with today. So it's an entire uh different uh uh environment right now. Uh I tell you, I don't know how to do with this uh because the significant change. But I can share uh some experience I had before. Uh so uh once a while uh the funding can uh significantly low, and uh uh after that normally the funding bouncing back. Okay. I hope uh that's the case. Uh I experienced several times uh like that. So uh when the funding is tight, uh so the uh the lab size uh is small, actually uh uh uh you will have more time to read the literature to think. So uh my own experience uh is uh when the lab is small, we publish critical papers. When you have a lot of money, a lot of people, you are busy with management. And uh uh without much time to think, actually, uh you publish something and then you go back a few like a lot of papers. It doesn't mean much. Okay. Uh so uh when the funding is tight and uh the lab is small, uh, I think uh read more and more discussion. Uh do not launch too many experiments very costly. Consume your resources. Instead, uh thinking carefully, just conduct uh the key experiment, address key hypotheses. I think uh uh uh that's the thing. What we learned uh uh in the past uh actually uh uh will worked well. Uh uh once you pass that time. I think the funding will come back eventually.

SPEAKER_01 19:03

I I like that. You kind of turn the challenge on your head and and view it as an opportunity. And I'd like to also a little bit talk about your experience as a mentor because I know that you've had many successful trainees come out of your lab. Are there any signature pearls that you try to impart as a mentor to the people training in your lab? What are the features of successful people when they were trainees? Um, I'd just love for you to talk in that area.

SPEAKER_00 19:34

Yeah, but I think uh uh uh that's something uh not easy training uh uh uh a good uh scientist in the lab. So first uh 10 years uh uh uh I experienced a lot of uh uh challenges how to do that. But uh recent years uh uh I have something uh uh useful I think uh share with uh everybody. Uh uh so uh I think uh the person has to be motivated. To motivate them, I think is the science, the topic that determines uh the training tenure time of the person in the lab. So normally uh what I find uh uh do not uh let a trainee to do experiments uh you don't understand, they feel like uh is an expedition interest. So now what I learned first choose a good question. Uh so lab already choose an area. So the good question you can propose to the uh postal or PhD student, they will uh I ask them to read the literature based on the question, make a hypothesis. Okay. Uh uh I discourage them without uh understanding and good hypothesis, began launch a lot of experiments. Uh so uh they make a hypothesis, then we discuss. Then I point out uh this is uh not a real hypothesis, it's a summary of other papers' uh result. So then they learn and gradually. Uh once uh we have a consensus of the hypothesis, so then we try to identify a key experiment to support the hypothesis. That is kind of hard, okay. Not for the trainee, for myself. But uh, I fully expose the hypothesis and let them read to come up. We have uh uh we give them a month's uh time, even longer, uh, to think and discuss. I believe uh doing research is a matter of idea. Uh it's not just uh keep doing experiment all the time. So I let them propose uh a key experiment. Uh so they come to a key experiment, so then we agree. So then the conduct experiment. I think in that way uh uh uh they are uh uh uh uh activated and so uh they are mentally uh thinking this while uh prepared experiment. So once that uh going on, so uh the key experiment uh uh we proposed really come along with the hypothesis. So uh we're all excited. Uh so uh then uh I told them this is a trick. Hi hypothesis-driven experiment. Continue. What is the next important question? Based on hypothesis. Now uh they are uh excited uh uh for thinking. So not uh uh only use their hands, they began use their uh uh knowledge and uh process uh uh the result along the knowledge and uh discuss with me. So that uh makes that person very exciting and continue work. Uh so hypothesis-driven experiment is uh the poor if uh there is one. So uh uh normally I don't uh uh assign uh experiment to them. So uh uh so I let them uh uh to propose the experiment, but the hypothesis has to be a good one. Uh and uh the hypothesis can be modified. And uh uh so I think that's uh uh uh important tool. So once they get trained, they uh set up their independent lab, uh, they got a habit, they believe what the research is an idea. It's not just doing a lot of experiments. And uh so that's why we trained probably uh, I did not count over 30 or 70 uh people outside as uh independent faculty. They are very competitive. Uh they they try to continue this uh uh hypothesis-driven uh uh experimental design.

unknown 24:09

Yeah.

SPEAKER_01 24:10

Yeah, so it sounds like uh a lot of closely supervised independence walking people through the scientific process and kind of emphasizing thinking more than just just doing.

SPEAKER_00 24:23

Yeah, exactly. I think uh thinking is uh uh uh more important.

SPEAKER_01 24:30

It certainly seemed to be successful for the people coming out of your hopefully uh they will, yeah. So maybe to close out, is there any you know final parting words or uh any anything that we haven't covered that you think we should?

SPEAKER_00 24:47

Okay, uh uh uh I enjoy uh the question uh you asked. Uh that's exactly uh what I have to share. But finally, uh uh I I want to see uh bone and uh scalar system uh is really interesting, and uh uh it has uh everything uh you can uh uh tell is stem cells, uh and the nerve and joint and uh a major disease. Uh we don't have an answer yet, okay. And uh uh uh so uh our recent uh finding, I always think bone is the largest, heaviest uh organ in the uh living system in humans. So uh in the past uh less uh uh understanding how our brain understanding bone homeostasis and uh control its metabolism. But uh recently we found uh actually PGE dictate the bone remodeling, reflect to the level of PGE. That one uh can precisely perceived by our brain, which is called a skeletal interception. And once the signal brings to the brain, so the brain can modulate endocrine system and uh other areas of the brain to coordinate orchestrate uh the all the activity. What we found actually is brain regulation uh is uh uh is uh uh upstream, okay, for many cases so far, and big time. Uh for example, uh if you do exercise, so PG2 is higher, through interest eruption, and come to the brain. If you have uh a skeletal disorder, PG2 is very high, it uh uh elevate uh the signaling as a protection of pain. So uh so far uh uh uh at this point uh uh we found uh still bone remodeling, osteoclaster uh uh uh you know modulate uh bone remodeling. Uh brain can uh perceive the changes. Osteoclaster initiated uh all the changes. So uh I studied coupling osteoclass. Now uh uh I try to understand the brain, and orthocluster is the conductor of orchestry of uh uh bone remodeling. So brain can uh communicate directly uh through uh uh 2cluster, not directly by uh PGE2, nitrogen one, this kind of thing. So uh for uh for my own uh career study, I think uh uh this is just the beginning. Uh I don't know how uh many years I continue to work on this, but uh uh uh I feel this is an interesting area. Uh I think it's just the beginning. Hopefully, more people will join and uh we work together uh uh for the uh brain modulation of phone.

SPEAKER_01 28:02

Yeah, I I think we see your fingerprints on that being uh uh a really hot area, an expanding area that a lot of investigators are interested in right now, for sure. Well, then uh I will thank Dr. Tao for taking the time to uh join us in this conversation today. Thank you so much.

SPEAKER_00 28:23

Okay, thank you, Matt, uh, for the opportunity uh for your questions uh and uh hopefully what I talked uh uh useful. Thank you again. Thank you.