Toward Stem Cell Therapies for Osteoporosis
The proximate cause of age-related osteoporosis is a growing imbalance between the distinct mechanisms and cell populations that are responsible for creating and breaking down bone tissue. It is plausible that delivering more cells capable of building bone may usefully patch over the situation to some degree - but it is only a patch, and it does only address this one majority cause of weakened bone in old people, and it does so without addressing the underlying causes, such as presence of senescent cells. Further, there are other unrelated causes of weakened bone in older individuals, including the persistent cross-linking of molecules in the bone extracellular matrix that makes bone less resilient. Nonetheless, as the authors here point out, a great many stem cell trials that might produce effects on the progression of osteoporosis are already taking place, without recording that data because they are focused on the treatment of other conditions. There is an opportunity to learn more about the utility of stem cell therapies for this condition with comparatively little additional effort.
Osteoporosis is caused by an imbalance between the tightly regulated process of bone formation by osteoblasts and resorption by osteoclasts. Primary osteoporosis is defined as bone loss attributed to aging or a decline in sex hormones associated with aging. This age-related osteoporosis involves the gradual loss of bone caused by insufficient bone formation.
The lack of an overall mechanistic understanding of what drives age-related osteoporosis has hindered the development of anabolic therapy appropriately targeting the etiology of the disease. It is hypothesized that decrease in the number and function of bone and bone marrow (BM)-derived mesenchymal stromal cells (MSCs) - a heterogeneous population comprising skeletal stem cells (SSCs), osteoblastic cells, and fibroblasts - lies at the root of age-related bone loss. Specifically, age-related changes in the proliferative and differentiation capacity of BM-MSCs are suspected, and recent evidence suggests that the loss of SSCs, which are a rare subset of MSCs, could be the most relevant event in the progression of senile bone loss. Thus, treatment strategies aimed at replenishing the MSCs compartment - and by extension SSCs - or augmenting endogenous populations of these cells, could result in bone growth and combat age-related osteoporosis.
A number of preclinical studies have been undertaken to determine whether MSC-based cell transplantation can induce bone formation. We have recently reported that transplantation of unmodified, low-passage MSCs prevents age-related osteoporosis in a mouse model. At the 6-month time point, we showed that transplanted animals displayed markedly increased bone formation, as well as higher osteoclast numbers. This led to improved bone quality and turnover, and importantly, sustained microarchitectural competence. Complementary to our work, studies documenting proof of principal that MSC transplantation can prevent senile osteoporosis in mouse models of accelerated aging present consistent findings.
Before the full benefit of SSC therapy can be leveraged toward bone regeneration, certain basic, translational, and clinical scientific questions will need to be answered. First, SSCs have only recently been characterized in murine models, and aside from one study documenting a BM stromal cell possessing some properties of SSCs (the generation of the hematopoietic microenvironment), this cell remains unidentified. As such, the human SSC still needs to be located, and fully characterized for phenotypic characteristics and cell surface antigen profile. Second, once identified, methods need to be developed to ensure the cell can be harvested and expanded to clinically relevant quantities. Stem cells often lose their multipotent, and self-renewal capabilities soon after removal from their native environment, therefore techniques will need to be optimized to enable large scale culture. Finally, although the safety and tumorigenic profile of MSCs has been fully evaluated and deemed safe, necessary due diligence will need to be performed on SSCs.
With over 500 clinical trials using MSCs registered with clinicaltrials.gov and numerous others being conceived, there presents a tremendous opportunity to maximize the scientific value of these expensive, laborious studies. The ability to co-operate, and leverage the availability of large, well-characterized cohorts of patients receiving MSCs (or other cell therapy/regenerative medicine agents) will maximize resource utilization. The ubiquitous nature of age-related bone loss in humans makes it an ideal candidate for regenerative medicine. Thus, we propose an ancillary study for osteoporosis to assess bone formation gains after systemic MSC transplant. By teaming up with other, even multiple, clinical trials the necessary number of patients could be more readily reached. This innovative model could be used to assess stem cell effects on various diseases in patients with existing comorbidities and chronic disease from trials that would normally only focus on one of the patient disease states. Significant savings can be achieved using an ancillary model in cell therapy due to cost sharing of expensive cell isolation, manipulation, and patient delivery.