**8. MSCs in osteoporosis**

reported that the efficacy of MSCs transplantation group was significantly better than that of the pure medullary decompression group [50]. In another study, 100 patients with early-stage ANFH were recruited and randomly assigned to BMMSC treatment or CD treatment only [51], a similar result was observed, that is, this intervention was proved to be safe and more effective in delaying or avoiding FH collapse. In another study of eight patients with bilateral femoral head necrosis, the researchers performed the medullary decompression on one side, while on the other side medullary decompression MSCs transplantation. The Harris hip score (HHS) and VAS score of the MSCs transplantation group were significantly improved, and the results of MRI quantitative analysis showed a significant decrease in necrosis area [52]. Consistently, another study found that the group of MSCs had a significantly superior recov-

However, there have been reports of unsatisfactory success rates for end-stage osteonecrosis of the femoral head (ONFH), even with MSCs [54]. To improve the outcome, Zhao et al. describe a modified technique using BMSCs associated with porous tantalum rod implantation combined with vascularized iliac grafting for the treatment of end-stage ONFH, and they followed up for 5 years, and these authors found that Harris hip score was improved from 38.74 ± 5.88 points (range 22–50) to 77.23 ± 14.75 points (range 33–95) [55]. It is worthy to mention that, in this procedure, approximately 10 mL of bone marrow from the subtrochanteric region was directly aspirated once the decompression tunnel was established during the surgery, avoiding the need for bone marrow aspiration from

Intervertebral disc degenerative is a serious worldwide problem for the aging population. The apoptosis of nucleus pulposus cells could be the main cause of intervertebral disc degeneration, with a variety of manifestations, that is, reduced number of the cells, the changes of the mechanical structure, down-regulated synthesis of matrix components (such as proteoglycan), nucleus pulposus dehydration, and increased metabolic waste [56, 57]. Many treatment options have been proposed, including physical therapy, pain medication, epidural steroid drug injection, disc radiating, myeloid nucleation, intervertebral fusion, and intervertebral disc displacement. However, these therapeutic approaches aim only to relieve the symptoms of disc degeneration, not treat its underlying cause. MSCs transplantation provides a new therapeutic strategy for promoting proteoglycan synthesis, decelerating the course of disc

For example, Sobajima et al. reported that BMSCs was injected into the lumbar intervertebral disc of the New Zealand white rabbit, and found that the transplanted BMSCs survived and migrated to the fibrous ring after 24 weeks [58]. Hee et al. confirmed that BMSCs implantation and axial distraction may have a synergistic effect in reversing degenerative disc disease in the rabbit model [59]. Some scholars have discovered that drug stimulation can regulate the differentiation of nucleus pulposus MSCs into nucleus pulposus cell

ery of the early stages of necrosis [53].

216 Stromal Cells - Structure, Function, and Therapeutic Implications

**7. MSCs in intervertebral disc degeneration**

degeneration, and stimulating disc regeneration.

the iliac crest.

Osteoporosis is a common metabolic bone disease, characterized by loss of bone mass, bone density reduction, and bone structure damage, which leads to increased bone fragility and risks of bone fracture [62]. The exact underlying mechanisms of osteoporosis are still unclear, but a shift of the cell differentiation of MSCs to adipocytes rather than osteoblasts partly contributes to osteoporosis [63]. Furthermore, it was observed that osteoclast activity (bone resorption) was enhanced, while osteoblast function (bone formation) decreased. For this reason, the drugs that inhibit the activity of osteoclasts have been widely used in clinical practice; however, these drugs have many complications, such as mandibular necrosis, reflux esophagitis, and atypical fracture [62, 64]. Recently, it is found that the decrease of BMSC to osteogenic differentiation and the increase of lipid differentiation is an important factor in the pathogenesis of osteoporosis [65, 66], therefore, one of the new ways to inhibit osteoporosis is to promote osteogenesis differentiation of endogenous BMSCs. In the meantime, BMSCs transplantation can also effectively increase bone mass and density, increase bone mechanical strength, correct the imbalance in bone metabolism, and increase bone formation, and is expected to provide a new strategy and method for the treatment of osteoporosis [67].

Scholars have carried out a large number of studies, including signal transduction, gene transcription, and post-transcriptional level, and found that miRNA and epigenetic modifications are probably the main mechanisms for BMSC differentiation [63]. In addition, conserved signal regulation, mechanical stimuli, radiation, and diet also play important roles in regulating the differentiation fate of MSCs. Even though an MSC transplant could, at least in theory, provide a treatment for osteoporosis, the clinical trials of MSCs in osteoporosis have just begun; nevertheless, the animal studies have already found that autograft or allogeneic MSC transplantation can increase the bone mass of animal models of osteoporosis [66, 67]. Since osteoporosis is a systemic disease, and the hormone levels and cytokines have changed dramatically, it is still unclear whether the simple local MSC transplantation can improve these changes in the long-term. In addition, the bone marrow homing efficiency of MSCs and the long-term survival of MSCs are still uncertain.

**Acknowledgements**

**Conflict of interest**

**Author details**

Jiazhao Yang1

**References**

and Lixin Kan2,3\*

China, Hefei, Anhui, China

Anhui province (1508085MC45).

The authors declare no competing interests.

, Shiyuan Fang1

DOI: 10.1002/jor.1100090504

, Lei Xu1

\*Address all correspondence to: l-kan@northwestern.edu

, Li Li1

2 School of Basic Medical Sciences, Anhui Medical University, Hefei, China

10.1002/(SICI)1097-4652(199910)181:1<67::AID-JCP7>3.0.CO;2-C

3 Department of Neurology, Northwestern University, Chicago, USA

, Kai Xie1

1 Department of Orthopedics, The First Hospital of University of Science and Technology of

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, Xujin Wang1

We appreciate the help from many members of the Kessler lab. LK was supported in part by national natural science foundation of China (81472087) and natural science foundation of
